dbSNP rs6413413: ADH1B:p.Thr60Ser (chr4-99318127-T-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000668.6(ADH1B):c.178A>T(p.Thr60Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,613,824 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0071 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 79 hom. )

Consequence

ADH1B
NM_000668.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.83

Publications

22 publications found

Variant links:

Genes affected

ADH1B (HGNC:250): (alcohol dehydrogenase 1B (class I), beta polypeptide) The protein encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ADH1B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034271777).

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1B	NM_000668.6 link	c.178A>T	p.Thr60Ser	missense_variant	Exon 3 of 9	ENST00000305046.13	NP_000659.2	P00325-1V9HW50
ADH1B	NM_001286650.2 link	c.58A>T	p.Thr20Ser	missense_variant	Exon 4 of 10		NP_001273579.1	P00325-2D6RHZ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1B	ENST00000305046.13 link	c.178A>T	p.Thr60Ser	missense_variant	Exon 3 of 9	1	NM_000668.6	ENSP00000306606.8		P00325-1

Frequencies

GnomAD3 genomes

AF:

0.00712

AC:

1081

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000919

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00461

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0437

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00707

Gnomad OTH

AF:

0.00672

GnomAD2 exomes

AF:

0.00757

AC:

1902

AN:

251370

AF XY:

0.00764

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0390

Gnomad NFE exome

AF:

0.00700

Gnomad OTH exome

AF:

0.00635

GnomAD4 exome

AF:

0.00744

AC:

10882

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

5265

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33476

American (AMR)

AF:

0.00313

AC:

140

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00189

AC:

163

AN:

86258

European-Finnish (FIN)

AF:

0.0357

AC:

1908

AN:

53420

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00725

AC:

8061

AN:

1111972

Other (OTH)

AF:

0.00684

AC:

413

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

693

1385

2078

2770

3463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00711

AC:

1081

AN:

151986

Hom.:

Cov.:

AF XY:

0.00883

AC XY:

656

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.000916

AC:

AN:

41480

American (AMR)

AF:

0.00460

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00229

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0437

AC:

462

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00708

AC:

481

AN:

67984

Other (OTH)

AF:

0.00665

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00583

Hom.:

Bravo

AF:

0.00415

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00659

AC:

800

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00682

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0020

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.0075

.;T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.23

.;T;.;T

MetaRNN

Benign

0.0034

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

-4.8

PrimateAI

Benign

0.27

PROVEAN

Benign

0.010

N;.;.;.

REVEL

Benign

0.017

Sift

Benign

0.74

T;.;.;.

Sift4G

Benign

0.33

T;T;T;.

Vest4

0.060

MutPred

0.23

Loss of glycosylation at T60 (P = 0.0394);.;.;Loss of glycosylation at T60 (P = 0.0394);

MVP

0.13

MPC

0.15

ClinPred

0.0032

GERP RS

-8.8

gMVP

0.26

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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rs6413413

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over