VCV001459499.5 - ClinVar

NC_000016.9:g.(?_97132)_(163851_?)del

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.

(1)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000016.9:g.(?_97132)_(163851_?)del

Variation ID: 1459499 Accession: VCV001459499.5

Type and length

Deletion, 66,720 bp

Location

Cytogenetic: 16p13.3 16: 97132-163851 (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	Mar 28, 2022	Jun 9, 2024	Feb 21, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_000016.9:g.(?_97132)_(163851_?)del

Protein change

Other names

Canonical SPDI

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.

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

Links

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.
NPRL3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	168	1073
HBA2		-	-	GRCh38 GRCh37	4	359
MPG		-	-	GRCh38 GRCh37	23	111
POLR3K		-	-	GRCh38 GRCh37	11	71
RHBDF1		-	-	GRCh38 GRCh37	95	162
SNRNP25	-	-	-	GRCh38 GRCh37	11	73

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 provided	Pathogenic (1)	criteria provided, single submitter	Feb 21, 2022	RCV001963099.6

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.
Pathogenic (Feb 21, 2022)	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: SCV002246549.4 First in ClinVar: Mar 28, 2022 Last updated: Jun 09, 2024	Publications: PubMed (8) PubMed: 7620173‚ 2253879‚ 8248238‚ 19696202‚ 20110179‚ 20580289‚ 20864588‚ 26915575 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that deletion of this regulatory region (known as HS40, MCS-2, MCS-R, … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that deletion of this regulatory region (known as HS40, MCS-2, MCS-R, and MSC-R2) results in severely reduced, although not absent, alpha-globin gene expression (PMID: 7620173, 2253879, 8248238, 19696202). This variant has been observed in individuals with alpha-thalassemia and HbH disease (PMID: 20110179, 20580289, 20864588, 26915575). It has also been observed to segregate with disease in related individuals. This variant is a gross deletion of the genomic region encompassing a regulatory region (HS40) located approximately 40kb upstream of the alpha globin gene cluster. It does not change the encoded amino acid sequence of the HBA1 or HBA2 proteins, but has been reported to affect alpha globin gene expression. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that deletion of this regulatory region (known as HS40, MCS-2, MCS-R, and MSC-R2) results in severely reduced, although not absent, alpha-globin gene expression (PMID: 7620173, 2253879, 8248238, 19696202). This variant has been observed in individuals with alpha-thalassemia and HbH disease (PMID: 20110179, 20580289, 20864588, 26915575). It has also been observed to segregate with disease in related individuals. This variant is a gross deletion of the genomic region encompassing a regulatory region (HS40) located approximately 40kb upstream of the alpha globin gene cluster. It does not change the encoded amino acid sequence of the HBA1 or HBA2 proteins, but has been reported to affect alpha globin gene expression.

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 selective deletion of the major α-globin regulatory element (MCS-R2) causing α-thalassaemia.	Wu MY	British journal of haematology	2017	PMID: 26915575
Homozygous deletion of the major alpha-globin regulatory element (MCS-R2) responsible for a severe case of hemoglobin H disease.	Sollaino MC	Blood	2010	PMID: 20864588
Novel large deletions in the human alpha-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment.	Coelho A	Blood cells, molecules & diseases	2010	PMID: 20580289
Thalassemia in Western Australia: 11 novel deletions characterized by Multiplex Ligation-dependent Probe Amplification.	Phylipsen M	Blood cells, molecules & diseases	2010	PMID: 20110179
Chromosome looping at the human alpha-globin locus is mediated via the major upstream regulatory element (HS -40).	Vernimmen D	Blood	2009	PMID: 19696202
Targeted inactivation of the major positive regulatory element (HS-40) of the human alpha-globin gene locus.	Bernet A	Blood	1995	PMID: 7620173
Analysis of the human alpha-globin gene cluster in transgenic mice.	Sharpe JA	Proceedings of the National Academy of Sciences of the United States of America	1993	PMID: 8248238
A major positive regulatory region located far upstream of the human alpha-globin gene locus.	Higgs DR	Genes & development	1990	PMID: 2253879

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000016.9:g.(?_97132)_(163851_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...