VCV000015680.2 - ClinVar

NC_000016.10:g.174045_192395del

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000016.10:g.174045_192395del

Variation ID: 15680 Accession: VCV000015680.2

Type and length

Deletion, 18,351 bp

Location

Cytogenetic: 16p13.3 16: 174045-192395 (GRCh38) [ 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	Apr 4, 2013	Nov 13, 2022	Jun 1, 2003

HGVS

Nucleotide	Protein	Molecular consequence
NC_000016.10:g.174045_192395del

Protein change

Other names

HBA2, METHYLATION SILENCING DUE TO ANTISENSE TRANSCRIPT

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

OMIM: 141850.0057 VarSome

Comment on variant

NCBI staff provided an HGVS expression for OMIM allelic variant 141850.0057 from the statement in the paper by Barbour et al., 2000 (PubMed 10910890) that "breakpoints lie between coordinates 164 044-45 and 182 395-96". Their numbering system is based on the placement of Z84812.1, which is offset by 10000 N in NC_000016.10.

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.
HBA1		-	-	GRCh38 GRCh37	5	392
HBA2		-	-	GRCh38 GRCh37	4	347
HBQ1		-	-	GRCh38 GRCh37	10	88
LOC106804613	-	-	-	GRCh38	1	329
LOC130058090	-	-	-	GRCh38	-	32
LOC130058091	-	-	-	GRCh38	-	28
LUC7L		-	-	GRCh38 GRCh37	26	94

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.
Alpha-thalassemia, zf type	Pathogenic (1)	no assertion criteria provided	Jun 1, 2003	RCV000016969.27

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 (Jun 01, 2003)	no assertion criteria provided Method: literature only	ALPHA-THALASSEMIA, ZF TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037241.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 13, 2022	Publications: PubMed (3) PubMed: 10910890‚ 12730694‚ 35190856 Comment on evidence: Barbour et al. (2000) reported an individual (called ZF) with alpha-thalassemia due to a unique deletion (called alpha(-)-ZF) that removed the HBA1 gene (141800) and … (more) Barbour et al. (2000) reported an individual (called ZF) with alpha-thalassemia due to a unique deletion (called alpha(-)-ZF) that removed the HBA1 gene (141800) and the HBQ1 gene (142240) and juxtaposed a region that normally lies approximately 18 kb downstream of the alpha-globin cluster to a site next to the structurally normal HBA2 gene. The alpha(-)-ZF deletion did not remove any positive cis-acting sequences, but expression of the structurally intact alpha-globin gene was stably silenced and, during development, its CpG island became densely methylated and insensitive to endonucleases over a region of approximately 2 kb. Tufarelli et al. (2003) showed that the deletion had truncated the widely expressed gene LUC7L (607782), which is transcribed from the opposite DNA strand. They showed that in the affected individual, in a transgenic model, and in differentiating embryonic stem cells, transcription of antisense RNA mediated silencing and methylation of the associated CpG island. This was identified as a novel mechanism underlying human genetic disease. In a review of epimutation mechanisms in metabolic disorders including ZF-type alpha-thalassemia, Gueant et al. (2022) discussed that, in a mouse stem cell model, promotor methylation was triggered by antisense LUC7L transcription, which occurred during cell differentiation (as opposed to the epimutation being present in germ cells). Thus, the epimutation was not considered to be constitutional. (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Epimutation in inherited metabolic disorders: the influence of aberrant transcription in adjacent genes.	Guéant JL	Human genetics	2022	PMID: 35190856
Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease.	Tufarelli C	Nature genetics	2003	PMID: 12730694
alpha-thalassemia resulting from a negative chromosomal position effect.	Barbour VM	Blood	2000	PMID: 10910890

Text-mined citations for this variant ...

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NC_000016.10:g.174045_192395del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...