rs1789915

chr4-99345214-A-G

Variant summary

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

The NM_000669.5(ADH1C):c.312T>C(p.Cys104=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,612,418 control chromosomes in the GnomAD database, including 70,442 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 0.23 (4904 hom., cov: 34)
  • Exomes 𝑓: 0.29 (65538 hom.)
• Consequence: ADH1C NM_000669.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770

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=-0.61).
• BP7: Synonymous conserved (PhyloP=-0.077 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH1C	NM_000669.5	c.312T>C	p.Cys104=	synonymous_variant	4/9	ENST00000515683.6
ADH1C	NR_133005.2	n.383T>C		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH1C	ENST00000515683.6	c.312T>C	p.Cys104=	synonymous_variant	4/9	1	NM_000669.5	P1
ADH1C	ENST00000510055.5	c.192T>C	p.Cys64=	synonymous_variant	5/7	3
ADH1C	ENST00000511397.3	c.210T>C	p.Cys70=	synonymous_variant	3/5	3
ADH1C	ENST00000505942.2	n.335T>C		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35417 AN: 152104 Hom.: 4901 Cov.: 34

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0215

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.206

GnomAD3 exomes AF: 0.243 AC: 60620 AN: 249662 Hom.: 8522 AF XY: 0.247 AC XY: 33391 AN XY: 134994

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.0201

Gnomad SAS exome AF: 0.219

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.290 AC: 423388 AN: 1460196 Hom.: 65538 Cov.: 39 AF XY: 0.288 AC XY: 208888 AN XY: 726320

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.0152

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.372

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.233 AC: 35428 AN: 152222 Hom.: 4904 Cov.: 34 AF XY: 0.231 AC XY: 17172 AN XY: 74402

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.0216

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.204

Alfa AF: 0.273 Hom.: 2708

Bravo AF: 0.213

Asia WGS AF: 0.113 AC: 394 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	9.0
Dann	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs1789915; hg19: chr4-100266371; COSMIC: COSV72463518;