rs1789915

Variant names:

• chr4-99345214-A-G
• rs1789915
• NM_000669.5:c.312T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000669.5(ADH1C):​c.312T>C​(p.Cys104Cys) 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
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000669.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	NM_000669.5	MANE Select	c.312T>C	p.Cys104Cys	synonymous	Exon 4 of 9	NP_000660.1	P00326
	ADH1C	NR_133005.2		n.383T>C		non_coding_transcript_exon	Exon 4 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	ENST00000515683.6	TSL:1 MANE Select	c.312T>C	p.Cys104Cys	synonymous	Exon 4 of 9	ENSP00000426083.1	P00326
	ADH1C	ENST00000865215.1		c.312T>C	p.Cys104Cys	synonymous	Exon 5 of 10	ENSP00000535274.1
	ADH1C	ENST00000865216.1		c.312T>C	p.Cys104Cys	synonymous	Exon 5 of 10	ENSP00000535275.1

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

GnomAD2 exomes AF: 0.243 AC: 60620 AN: 249662 AF XY: 0.247

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 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

African (AFR) AF: 0.111 AC: 3728 AN: 33468

American (AMR) AF: 0.179 AC: 7983 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5720 AN: 26120

East Asian (EAS) AF: 0.0152 AC: 605 AN: 39690

South Asian (SAS) AF: 0.216 AC: 18620 AN: 86134

European-Finnish (FIN) AF: 0.372 AC: 19841 AN: 53358

Middle Eastern (MID) AF: 0.206 AC: 1182 AN: 5750

European-Non Finnish (NFE) AF: 0.315 AC: 349700 AN: 1110718

Other (OTH) AF: 0.265 AC: 16009 AN: 60324

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

African (AFR) AF: 0.117 AC: 4851 AN: 41566

American (AMR) AF: 0.198 AC: 3031 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 774 AN: 3472

East Asian (EAS) AF: 0.0216 AC: 112 AN: 5190

South Asian (SAS) AF: 0.195 AC: 941 AN: 4828

European-Finnish (FIN) AF: 0.371 AC: 3914 AN: 10560

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21138 AN: 68000

Other (OTH) AF: 0.204 AC: 431 AN: 2108

Alfa AF: 0.240 Hom.: 3645

Bravo AF: 0.213

Asia WGS AF: 0.113 AC: 394 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.0
DANN	Benign	0.67
PhyloP100		-0.077

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

Other links and lift over

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