chr4-99307860-G-A

Variant names:

Variant summary

Our verdict is The variant received -9 classification points (ACMG Germline Pathogenicity v2019). BA1BP4

The NM_000668.6(ADH1B):c.1108C>T (p.Arg370Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0109 (AC=17,612) in the gnomAD database across 1,613,550 control chromosomes, including 1,461 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.193. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.054 ( 756 hom., cov: 32)

Exomes 𝑓: 0.0064 ( 705 hom. )

Consequence

ADH1B
NM_000668.6 missense

Scores

Clinical Significance

protective no assertion criteria provided B:1

Conservation

PhyloP100: 3.37

Publications

145 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 Gene-Disease associations (from GenCC):

alcohol dependence
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

ADH1B links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000668.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -9 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1929 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000668.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1B	NM_000668.6	MANE Select	c.1108C>T	p.Arg370Cys	missense	Exon 9 of 9	NP_000659.2
	ADH1B	NM_001286650.2		c.988C>T	p.Arg330Cys	missense	Exon 10 of 10	NP_001273579.1	D6RHZ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADH1B	ENST00000305046.13	TSL:1 MANE Select	c.1108C>T	p.Arg370Cys	missense	Exon 9 of 9	ENSP00000306606.8	P00325-1
ADH1B	ENST00000625860.2	TSL:1	c.988C>T	p.Arg330Cys	missense	Exon 9 of 9	ENSP00000486614.1	P00325-2
ADH1B	ENST00000881106.1		c.1141C>T	p.Arg381Cys	missense	Exon 9 of 9	ENSP00000551165.1	A0ACI8S9I4

Frequencies

GnomAD3 genomes

AF:

0.0545

AC:

8277

AN:

151978

Hom.:

757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.0393

GnomAD2 exomes

AF:

0.0150

AC:

3780

AN:

251340

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.00885

Gnomad ASJ exome

AF:

0.00823

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00163

Gnomad OTH exome

AF:

0.00766

GnomAD4 exome

AF:

0.00638

AC:

9326

AN:

1461454

Hom.:

705

Cov.:

AF XY:

0.00566

AC XY:

4116

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.197

AC:

6552

AN:

33286

American (AMR)

AF:

0.00953

AC:

426

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00742

AC:

194

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00139

AC:

120

AN:

86248

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00113

AC:

1255

AN:

1111854

Other (OTH)

AF:

0.0119

AC:

716

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

387

774

1160

1547

1934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.0545

AC:

8286

AN:

152096

Hom.:

756

Cov.:

AF XY:

0.0529

AC XY:

3936

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.188

AC:

7803

AN:

41458

American (AMR)

AF:

0.0171

AC:

261

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

67996

Other (OTH)

AF:

0.0389

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

351

702

1052

1403

1754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0179

Hom.:

523

Bravo

AF:

0.0624

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00302

Local populations

Turkish Variome

AF:

0.00491

AC:

AN:

6716

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000112

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0354

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:protective

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alcohol dependence (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.45

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

PhyloP100

3.4

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.9

REVEL

Benign

0.19

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.017

gMVP

0.85

Mutation Taster

=72/28

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over