VCV000015070.14 - ClinVar

NM_000519.4(HBD):c.82G>T (p.Ala28Ser)

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
Pathogenic(3); Likely pathogenic(1); 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_000519.4(HBD):c.82G>T (p.Ala28Ser)

Variation ID: 15070 Accession: VCV000015070.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 5234352 (GRCh38) [ NCBI UCSC ] 11: 5255582 (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	Apr 4, 2013	Oct 8, 2024	Sep 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000519.4:c.82G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000510.1:p.Ala28Ser	missense
NC_000011.10:g.5234352C>A
NC_000011.9:g.5255582C>A
NG_000007.3:g.63264G>T
NG_042297.1:g.469C>A
NG_053024.1:g.20C>A
NG_063112.2:g.14306G>T
LRG_1335:g.14306G>T
LRG_1335t1:c.82G>T	LRG_1335p1:p.Ala28Ser
	P02042:p.Ala28Ser

... more HGVS ... less HGVS

Protein change

A28S

Other names

A27S
HBD:c.82G>T

Canonical SPDI

NC_000011.10:5234351:C: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.

0.00100 (A)

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

1000 Genomes Project 0.00100

1000 Genomes Project 30x 0.00109

The Genome Aggregation Database (gnomAD) 0.00158

Trans-Omics for Precision Medicine (TOPMed) 0.00161

The Genome Aggregation Database (gnomAD), exomes 0.00216

Exome Aggregation Consortium (ExAC) 0.00223

Links

HBVAR: 660 ClinGen: CA124682 UniProtKB: P02042#VAR_003105 OMIM: 142000.0028 dbSNP: rs35152987 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.
HBD		-	-	GRCh38 GRCh37	34	115
LOC106099063	-	-	-	GRCh38	-	43

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.
delta Thalassemia	Pathogenic (2)	no assertion criteria provided	Jan 6, 2020	RCV000016221.28
HEMOGLOBIN A(2) YIALOUSA	other (1)	no assertion criteria provided	Dec 12, 2017	RCV000016222.2
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 17, 2024	RCV000398301.8
Fetal hemoglobin quantitative trait locus 1	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001107109.4
Glucocorticoid-remediable aldosteronism	Likely pathogenic (1)	criteria provided, single submitter	Mar 17, 2024	RCV003987322.3

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 (Jul 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004236133.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fetal hemoglobin quantitative trait locus 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001264239.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 3401592‚ 16434382 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Glucocorticoid-remediable aldosteronism Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804765.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Sep 17, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000330244.8 First in ClinVar: Dec 06, 2016 Last updated: Oct 08, 2024	Comment: Commonly referred to as the Hb A2-Yialousa variant and has been reported numerous times in the literature and is the most common variant identified in … (more) Commonly referred to as the Hb A2-Yialousa variant and has been reported numerous times in the literature and is the most common variant identified in the HBD gene in individuals from the Mediterranean area (PMID: 26754299, 23797957, 23215833, 1742490, 3401592); Published functional studies demonstrate that this variant may affect RNA splicing by strengthening an upstream cryptic splice donor site (PMID: 8900178); In silico analysis supports that this missense variant has a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12402333, 3401592, 1742490, 9054695, 23215833, 1398286, 25333069, 27884173, 20854114, 26754299, 27461962, 23797957, 30487145, 31980526, 34426522, 31688628, 31589614, 33178177, 10975439, 35930292, 37605839, 8900178) (less)
Pathogenic (Jun 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005046494.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Number of individuals with the variant: 5
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	delta Thalassemia Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142416.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Comment: NM_000519.3:c.82G>T in the HBD gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database. The HBD c.82G>T (p.Ala28Ser) was the … (more) NM_000519.3:c.82G>T in the HBD gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database. The HBD c.82G>T (p.Ala28Ser) was the most common variant found in the HBD gene in a Iran cohort with thalassemia (PMID: 26754299). In addition, De Angioletti et al. also reported that the Hb A2-Yialousa (g.82G>T) was the most prevalent (42/63 families). Functional studies indicate that A28S may affect RNA splicing by strengthening an upstream cryptic splice donor site (PMID: 1742490). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PP4; PS3. (less)
Pathogenic (Nov 01, 2002)	no assertion criteria provided Method: literature only	DELTA-THALASSEMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036489.3 First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018	Publications: PubMed (4) PubMed: 1398286‚ 3401592‚ 1742490‚ 12402333 Comment on evidence: Renda et al. (1992) demonstrated homozygosity for a G-to-T transversion at the first nucleotide of codon 27 of the delta-globin gene in a Sicilian woman. … (more) Renda et al. (1992) demonstrated homozygosity for a G-to-T transversion at the first nucleotide of codon 27 of the delta-globin gene in a Sicilian woman. This mutation had first been demonstrated in Sardinia by Moi et al. (1988). In an attempt to identify mutations that might be the basis of delta-thalassemia, Trifillis et al. (1991) amplified by PCR the HBD region from 3 Greek Cypriot families and determined the DNA sequence. Four novel mutations were identified. One of these was a G-to-T transversion at codon 27 resulting in an alanine to serine change. The G-to-T change presumably activates a cryptic splice site resulting in aberrant transcript processing. De Angioletti et al. (2002) found this variant in 42 of 63 families in 2 regions of southern Italy. (less)
other (Dec 12, 2017)	no assertion criteria provided Method: literature only	HEMOGLOBIN A(2) YIALOUSA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036490.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 1398286‚ 3401592‚ 1742490‚ 12402333 Comment on evidence: Renda et al. (1992) demonstrated homozygosity for a G-to-T transversion at the first nucleotide of codon 27 of the delta-globin gene in a Sicilian woman. … (more) Renda et al. (1992) demonstrated homozygosity for a G-to-T transversion at the first nucleotide of codon 27 of the delta-globin gene in a Sicilian woman. This mutation had first been demonstrated in Sardinia by Moi et al. (1988). In an attempt to identify mutations that might be the basis of delta-thalassemia, Trifillis et al. (1991) amplified by PCR the HBD region from 3 Greek Cypriot families and determined the DNA sequence. Four novel mutations were identified. One of these was a G-to-T transversion at codon 27 resulting in an alanine to serine change. The G-to-T change presumably activates a cryptic splice site resulting in aberrant transcript processing. De Angioletti et al. (2002) found this variant in 42 of 63 families in 2 regions of southern Italy. (less)

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Commonly referred to as the Hb A2-Yialousa variant and has been reported numerous times in the literature and is the most common variant identified in the HBD gene in individuals from the Mediterranean area (PMID: 26754299, 23797957, 23215833, 1742490, 3401592); Published functional studies demonstrate that this variant may affect RNA splicing by strengthening an upstream cryptic splice donor site (PMID: 8900178); In silico analysis supports that this missense variant has a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12402333, 3401592, 1742490, 9054695, 23215833, 1398286, 25333069, 27884173, 20854114, 26754299, 27461962, 23797957, 30487145, 31980526, 34426522, 31688628, 31589614, 33178177, 10975439, 35930292, 37605839, 8900178)

Comment:

NM_000519.3:c.82G>T in the HBD gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database. The HBD c.82G>T (p.Ala28Ser) was the most common variant found in the HBD gene in a Iran cohort with thalassemia (PMID: 26754299). In addition, De Angioletti et al. also reported that the Hb A2-Yialousa (g.82G>T) was the most prevalent (42/63 families). Functional studies indicate that A28S may affect RNA splicing by strengthening an upstream cryptic splice donor site (PMID: 1742490). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PP4; PS3.

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
Known and new delta globin gene mutations and their diagnostic significance.	Bouva MJ	Haematologica	2006	PMID: 16434382
Epidemiology of the delta globin alleles in southern Italy shows complex molecular, genetic, and phenotypic features.	De Angioletti M	Human mutation	2002	PMID: 12402333
Delta + 27 homozygosis in a Sicilian family.	Renda M	Haematologica	1992	PMID: 1398286
Identification of four novel delta-globin gene mutations in Greek Cypriots using polymerase chain reaction and automated fluorescence-based DNA sequence analysis.	Trifillis P	Blood	1991	PMID: 1742490
Delineation of the molecular basis of delta- and normal HbA2 beta-thalassemia.	Moi P	Blood	1988	PMID: 3401592

Text-mined citations for rs35152987 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000519.4(HBD):c.82G>T (p.Ala28Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35152987 ...