VCV000447517.18 - ClinVar

NM_175914.5(HNF4A):c.427-4G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_175914.5(HNF4A):c.427-4G>A

Variation ID: 447517 Accession: VCV000447517.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 44414503 (GRCh38) [ NCBI UCSC ] 20: 43043143 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	May 1, 2024	Oct 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_175914.5:c.427-4G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_000457.6:c.493-4G>A		intron variant
NM_001030003.3:c.427-4G>A		intron variant
NM_001030004.3:c.427-4G>A		intron variant
NM_001258355.2:c.472-4G>A		intron variant
NM_001287182.2:c.418-4G>A		intron variant
NM_001287183.2:c.418-4G>A		intron variant
NM_001287184.2:c.418-4G>A		intron variant
NM_178849.3:c.493-4G>A		intron variant
NM_178850.3:c.493-4G>A		intron variant
NC_000020.11:g.44414503G>A
NC_000020.10:g.43043143G>A
NG_009818.1:g.63703G>A
LRG_483:g.63703G>A
LRG_483t1:c.427-4G>A
LRG_483t2:c.493-4G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000020.11:44414502:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00639 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00021

Trans-Omics for Precision Medicine (TOPMed) 0.00036

1000 Genomes Project 30x 0.00547

1000 Genomes Project 0.00639

Links

ClinGen: CA9870269 dbSNP: rs146751799 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HNF4A		-	-	GRCh38 GRCh37	637	650

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	May 2, 2019	RCV000518191.9
not provided	Benign (2)	criteria provided, single submitter	Oct 17, 2023	RCV000901336.12
Type 2 diabetes mellitus	Likely benign (1)	criteria provided, single submitter	-	RCV001258240.5
Maturity onset diabetes mellitus in young	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Apr 27, 2021	RCV002226713.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Nov 14, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000613655.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (5) PubMed: 26059258‚ 23227446‚ 23268925‚ 10447526‚ 15281001
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Type 2 diabetes mellitus (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435152.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (1) PubMed: 15281001 Comment: The heterozygous c.427-4G>A variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young (PMID: 15281001), … (more) The heterozygous c.427-4G>A variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young (PMID: 15281001), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Computational prediction tools suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant diabetes mellitus type 2. (less)
Benign (May 02, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002066212.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Uncertain significance (-)	criteria provided, single submitter (K&H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria) Method: research	Maturity onset diabetes mellitus in young Affected status: unknown Allele origin: somatic	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002505493.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Publications: PubMed (2) PubMed: 35118593‚ 35052457 Comment: This mutation is associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin … (more) This mutation is associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, no sufficient evidence is found to ascertain the role of rs146751799 variant in Diabetes Mellitus yet. (less)
Benign (Oct 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001045702.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024
Benign (Apr 27, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Maturity onset diabetes mellitus in young Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002631740.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034108.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035422.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021

Comment:

The heterozygous c.427-4G>A variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young (PMID: 15281001), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Computational prediction tools suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant diabetes mellitus type 2.

Comment:

This mutation is associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, no sufficient evidence is found to ascertain the role of rs146751799 variant in Diabetes Mellitus yet.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A novel HNF4A mutation identified in a child with maturity onset diabetes of the young.	Zhu MQ	World journal of pediatrics : WJP	2022	PMID: 35118593
Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes.	Marucci A	Genes	2022	PMID: 35052457
Characteristics of maturity onset diabetes of the young in a large diabetes center.	Chambers C	Pediatric diabetes	2016	PMID: 26059258
Genetic variations of NR2A1 in Asian populations: implications in pharmacogenetics studies.	Chew SC	Drug metabolism and pharmacokinetics	2013	PMID: 23268925
Examination of Rare Variants in HNF4 α in European Americans with Type 2 Diabetes.	Hellwege JN	Journal of diabetes & metabolism	2011	PMID: 23227446
Triple genetic variation in the HNF-4alpha gene is associated with early-onset type 2 diabetes mellitus in a philippino family.	Gragnoli C	Metabolism: clinical and experimental	2004	PMID: 15281001
High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes.	Lehto M	Diabetologia	1999	PMID: 10447526

Text-mined citations for rs146751799 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_175914.5(HNF4A):c.427-4G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146751799 ...