rs35152987

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS2_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A28D) has been classified as Uncertain significance.

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:6U:1B:1O:1

Conservation

PhyloP100: 0.0400

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

delta-beta-thalassemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HBD links:

ENSG00000298932 (HGNC:):

ENSG00000298932 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000519.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	NM_000519.4	MANE Select	c.82G>T	p.Ala28Ser	missense	Exon 1 of 3	NP_000510.1	P02042

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HBD	ENST00000650601.1	MANE Select	c.82G>T	p.Ala28Ser	missense	Exon 1 of 3	ENSP00000497529.1	P02042
HBD	ENST00000643122.1		c.82G>T	p.Ala28Ser	missense	Exon 2 of 4	ENSP00000494708.1	P02042
HBD	ENST00000292901.7	TSL:3	c.82G>T	p.Ala28Ser	missense	Exon 1 of 3	ENSP00000292901.3	E9PFT6

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

GnomAD2 exomes

AF:

0.00216

AC:

542

AN:

251342

AF XY:

0.00241

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 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

African (AFR)

AF:

0.000299

AC:

AN:

33460

American (AMR)

AF:

0.00114

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00735

AC:

192

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00402

AC:

347

AN:

86250

European-Finnish (FIN)

AF:

0.00125

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00174

AC:

1938

AN:

1111666

Other (OTH)

AF:

0.00229

AC:

138

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

156

312

468

624

780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00163

AC:

249

AN:

152318

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41556

American (AMR)

AF:

0.00131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00269

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00201

AC:

137

AN:

68032

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00218

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

delta Thalassemia (2)

Fetal hemoglobin quantitative trait locus 1 (1)

Glucocorticoid-remediable aldosteronism (1)

Thalassemia (1)

HEMOGLOBIN A(2) YIALOUSA (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.015

MetaSVM

Uncertain

-0.049

MutationAssessor

Uncertain

2.4

PhyloP100

0.040

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.64

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.058

Polyphen

0.62

Vest4

0.78

MVP

0.85

MPC

0.046

ClinPred

0.059

GERP RS

-0.76

PromoterAI

0.14

Neutral

(source)

Varity_R

0.41

gMVP

0.72

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over