rs1693425

Positions:

• chr4-99344955-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000669.5(ADH1C):​c.474G>A​(p.Val158=) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.860

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.474G>A	p.Val158=	synonymous_variant	5/9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.545G>A		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.474G>A	p.Val158=	synonymous_variant	5/9	1	NM_000669.5	ENSP00000426083	P1
ADH1C	ENST00000510055.5	c.354G>A	p.Val118=	synonymous_variant	6/7	3		ENSP00000478439
ADH1C	ENST00000511397.3	c.372G>A	p.Val124=	synonymous_variant	4/5	3		ENSP00000478545
ADH1C	ENST00000505942.2	n.497G>A		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47467 AN: 151956 Hom.: 8851 Cov.: 32

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

GnomAD3 exomes AF: 0.345 AC: 86817 AN: 251430 Hom.: 16799 AF XY: 0.349 AC XY: 47401 AN XY: 135898

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 SAS exome AF: 0.326

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.: 79 AF XY: 0.385 AC XY: 279839 AN XY: 727232

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.323

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.0649

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.515

Gnomad4 NFE exome AF: 0.414

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.312 AC: 47488 AN: 152074 Hom.: 8857 Cov.: 32 AF XY: 0.313 AC XY: 23247 AN XY: 74330

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.0809

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.281

Alfa AF: 0.361 Hom.: 4671

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
DANN	Benign	0.50

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

LitVar

Other links and lift over

dbSNP: rs1693425; hg19: chr4-100266112; COSMIC: COSV72463410;