dbSNP rs1693425: ADH1C:p.Val158Val (chr4-99344955-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000669.5(ADH1C):c.474G>A(p.Val158Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,613,934 control chromosomes in the GnomAD database, including 124,699 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 8857 hom., cov: 32)

Exomes 𝑓: 0.39 ( 115842 hom. )

Consequence

ADH1C
NM_000669.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.860

Publications

18 publications found

Variant links:

Genes affected

ADH1C (HGNC:251): (alcohol dehydrogenase 1C (class I), gamma polypeptide) This gene encodes class I alcohol dehydrogenase, gamma subunit, which 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. Class I alcohol dehydrogenase, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation to acetaldehyde, thus playing 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. An association between ADH1C polymorphism and alcohol dependence has not been established. [provided by RefSeq, Sep 2019]

ADH1C links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP7

Synonymous conserved (PhyloP=-0.86 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5 link	c.474G>A	p.Val158Val	synonymous_variant	Exon 5 of 9	ENST00000515683.6	NP_000660.1	P00326
ADH1C	NR_133005.2 link	n.545G>A		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADH1C	ENST00000515683.6 link	c.474G>A	p.Val158Val	synonymous_variant	Exon 5 of 9	1	NM_000669.5	ENSP00000426083.1	P00326
ADH1C	ENST00000510055.5 link	c.354G>A	p.Val118Val	synonymous_variant	Exon 6 of 7	3		ENSP00000478439.1	A0A087WU81
ADH1C	ENST00000511397.3 link	c.372G>A	p.Val124Val	synonymous_variant	Exon 4 of 5	3		ENSP00000478545.1	A0A087WUC4
ADH1C	ENST00000505942.2 link	n.497G>A		non_coding_transcript_exon_variant	Exon 5 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47467

AN:

151956

Hom.:

8851

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.0813

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.513

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.412

Gnomad OTH

AF:

0.278

GnomAD2 exomes

AF:

0.345

AC:

86817

AN:

251430

AF XY:

0.349

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.327

Gnomad ASJ exome

AF:

0.265

Gnomad EAS exome

AF:

0.0781

Gnomad FIN exome

AF:

0.517

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.347

GnomAD4 exome

AF:

0.388

AC:

567064

AN:

1461860

Hom.:

115842

Cov.:

AF XY:

0.385

AC XY:

279839

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.134

AC:

4485

AN:

33480

American (AMR)

AF:

0.323

AC:

14432

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

7136

AN:

26136

East Asian (EAS)

AF:

0.0649

AC:

2577

AN:

39700

South Asian (SAS)

AF:

0.321

AC:

27716

AN:

86254

European-Finnish (FIN)

AF:

0.515

AC:

27505

AN:

53420

Middle Eastern (MID)

AF:

0.269

AC:

1551

AN:

5768

European-Non Finnish (NFE)

AF:

0.414

AC:

459951

AN:

1111984

Other (OTH)

AF:

0.359

AC:

21711

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

22597

45195

67792

90390

112987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13838

27676

41514

55352

69190

<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:

0.312

AC:

47488

AN:

152074

Hom.:

8857

Cov.:

AF XY:

0.313

AC XY:

23247

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.144

AC:

5971

AN:

41518

American (AMR)

AF:

0.292

AC:

4462

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

943

AN:

3468

East Asian (EAS)

AF:

0.0809

AC:

418

AN:

5166

South Asian (SAS)

AF:

0.296

AC:

1425

AN:

4808

European-Finnish (FIN)

AF:

0.513

AC:

5417

AN:

10560

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.412

AC:

27983

AN:

67974

Other (OTH)

AF:

0.281

AC:

591

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1577

3153

4730

6306

7883

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<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:

0.359

Hom.:

4683

Bravo

AF:

0.287

Asia WGS

AF:

0.220

AC:

764

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

1.8

(source)

DANN

Benign

0.50

PhyloP100

-0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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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