4-99342808-C-T

Variant names:

• chr4-99342808-C-T
• rs1693482
• NM_000669.5:c.815G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000669.5(ADH1C):​c.815G>A​(p.Arg272Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,612,334 control chromosomes in the GnomAD database, including 124,558 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.31 (8870 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115688 hom.)
• Consequence: ADH1C NM_000669.5 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 0.447
• Publications: 97 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.4730564E-5).
• 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	c.815G>A	p.Arg272Gln	missense_variant	Exon 6 of 9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.855+31G>A		intron_variant	Intron 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.815G>A	p.Arg272Gln	missense_variant	Exon 6 of 9	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.*118G>A		downstream_gene_variant		3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.*203G>A		downstream_gene_variant		3		ENSP00000478545.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47499 AN: 152058 Hom.: 8863 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0816

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.345 AC: 86408 AN: 250778 AF XY: 0.348

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.263

Gnomad EAS exome AF: 0.0777

Gnomad FIN exome AF: 0.517

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.347

GnomAD4 exome AF: 0.388 AC: 565821 AN: 1460158 Hom.: 115688 Cov.: 74 AF XY: 0.384 AC XY: 279183 AN XY: 726466

African (AFR) AF: 0.134 AC: 4474 AN: 33472

American (AMR) AF: 0.323 AC: 14434 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 7079 AN: 26104

East Asian (EAS) AF: 0.0649 AC: 2576 AN: 39700

South Asian (SAS) AF: 0.318 AC: 27445 AN: 86234

European-Finnish (FIN) AF: 0.515 AC: 27504 AN: 53416

Middle Eastern (MID) AF: 0.267 AC: 1536 AN: 5762

European-Non Finnish (NFE) AF: 0.413 AC: 459108 AN: 1110404

Other (OTH) AF: 0.359 AC: 21665 AN: 60352

GnomAD4 genome AF: 0.312 AC: 47519 AN: 152176 Hom.: 8870 Cov.: 33 AF XY: 0.313 AC XY: 23285 AN XY: 74400

African (AFR) AF: 0.144 AC: 5971 AN: 41528

American (AMR) AF: 0.293 AC: 4475 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 942 AN: 3468

East Asian (EAS) AF: 0.0812 AC: 421 AN: 5186

South Asian (SAS) AF: 0.294 AC: 1418 AN: 4826

European-Finnish (FIN) AF: 0.514 AC: 5431 AN: 10564

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27986 AN: 67996

Other (OTH) AF: 0.282 AC: 597 AN: 2114

Alfa AF: 0.370 Hom.: 10493

Bravo AF: 0.287

TwinsUK AF: 0.407 AC: 1511

ALSPAC AF: 0.397 AC: 1531

ESP6500AA AF: 0.150 AC: 660

ESP6500EA AF: 0.384 AC: 3304

ExAC AF: 0.342 AC: 41574

Asia WGS AF: 0.220 AC: 762 AN: 3478

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Alcohol dependence Benign:1

Jun 01, 2008

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.000065	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.45
PrimateAI	Benign	0.27	T
Sift4G	Uncertain	0.011	D
Polyphen		0.0020	B
Vest4		0.067
GERP RS		1.8
Varity_R		0.078
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1693482; hg19: chr4-100263965; COSMIC: COSV72463409; COSMIC: COSV72463409;