11-5234352-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000519.4(HBD):c.82G>T(p.Ala28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,613,812 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 16 hom. )

Consequence

HBD
NM_000519.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6B:1O:1

Conservation

PhyloP100: 0.0400

Variant links:

Genes affected

HBD (HGNC:4829): (hemoglobin subunit delta) The delta (HBD) and beta (HBB) genes are normally expressed in the adult: two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin. Two alpha chains plus two delta chains constitute HbA-2, which with HbF comprises the remaining 3% of adult hemoglobin. Five beta-like globin genes are found within a 45 kb cluster on chromosome 11 in the following order: 5'-epsilon--Ggamma--Agamma--delta--beta-3'. Mutations in the delta-globin gene are associated with beta-thalassemia. [provided by RefSeq, Jul 2008]

HBD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 16 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4 link	c.82G>T	p.Ala28Ser	missense_variant	Exon 1 of 3	ENST00000650601.1	NP_000510.1	P02042A0N071

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1 link	c.82G>T	p.Ala28Ser	missense_variant	Exon 1 of 3		NM_000519.4	ENSP00000497529.1		P02042

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00201

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00216

AC:

542

AN:

251342

Hom.:

AF XY:

0.00241

AC XY:

328

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000926

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00382

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00190

AC:

2775

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1523

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00735

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00402

Gnomad4 FIN exome

AF:

0.00125

Gnomad4 NFE exome

AF:

0.00174

Gnomad4 OTH exome

AF:

0.00229

GnomAD4 genome

AF:

0.00163

AC:

249

AN:

152318

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00201

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00258

Hom.:

Bravo

AF:

0.00161

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00223

AC:

271

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jun 24, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

delta Thalassemia

Pathogenic:2

Nov 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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. -

Glucocorticoid-remediable aldosteronism

Pathogenic:1

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Fetal hemoglobin quantitative trait locus 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

HEMOGLOBIN A(2) YIALOUSA

Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

T;T;T;T;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.81

T;.;.;T;D;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.015

T;T;T;T;T;T

MetaSVM

Uncertain

-0.049

MutationAssessor

Uncertain

2.4

.;M;M;M;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

N;.;N;.;N;N

REVEL

Uncertain

0.64

Sift

Uncertain

0.0080

D;.;D;.;D;D

Sift4G

Uncertain

0.058

T;.;T;.;D;.

Polyphen

0.62

.;P;P;P;.;.

Vest4

0.78

MVP

0.85

MPC

0.046

ClinPred

0.059

GERP RS

-0.76

Varity_R

0.41

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.56

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.56

Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over