4-99344976-T-C

Variant names:

• chr4-99344976-T-C
• rs2241894
• NM_000669.5:c.453A>G

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.453A>G​(p.Thr151Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,916 control chromosomes in the GnomAD database, including 70,561 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 (8988 hom., cov: 33)
  • Exomes 𝑓: 0.26 (61573 hom.)
• Consequence: ADH1C NM_000669.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.08
• Publications: 32 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=-0.96).
• BP7: Synonymous conserved (PhyloP=-6.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.453A>G	p.Thr151Thr	synonymous_variant	Exon 5 of 9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.524A>G		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.453A>G	p.Thr151Thr	synonymous_variant	Exon 5 of 9	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.333A>G	p.Thr111Thr	synonymous_variant	Exon 6 of 7	3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.351A>G	p.Thr117Thr	synonymous_variant	Exon 4 of 5	3		ENSP00000478545.1
ADH1C	ENST00000505942.2	n.476A>G		non_coding_transcript_exon_variant	Exon 5 of 5	5

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47308 AN: 151926 Hom.: 8988 Cov.: 33

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.292

GnomAD2 exomes AF: 0.297 AC: 74637 AN: 251412 AF XY: 0.306

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.765

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.261 AC: 381031 AN: 1461872 Hom.: 61573 Cov.: 76 AF XY: 0.268 AC XY: 195072 AN XY: 727236

African (AFR) AF: 0.472 AC: 15796 AN: 33478

American (AMR) AF: 0.144 AC: 6434 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 5030 AN: 26136

East Asian (EAS) AF: 0.823 AC: 32691 AN: 39700

South Asian (SAS) AF: 0.503 AC: 43408 AN: 86256

European-Finnish (FIN) AF: 0.168 AC: 8964 AN: 53416

Middle Eastern (MID) AF: 0.251 AC: 1446 AN: 5768

European-Non Finnish (NFE) AF: 0.226 AC: 251489 AN: 1111998

Other (OTH) AF: 0.261 AC: 15773 AN: 60396

GnomAD4 genome AF: 0.311 AC: 47336 AN: 152044 Hom.: 8988 Cov.: 33 AF XY: 0.317 AC XY: 23536 AN XY: 74342

African (AFR) AF: 0.460 AC: 19059 AN: 41430

American (AMR) AF: 0.214 AC: 3266 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 690 AN: 3472

East Asian (EAS) AF: 0.754 AC: 3878 AN: 5146

South Asian (SAS) AF: 0.534 AC: 2567 AN: 4806

European-Finnish (FIN) AF: 0.165 AC: 1748 AN: 10598

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15192 AN: 67988

Other (OTH) AF: 0.289 AC: 611 AN: 2112

Alfa AF: 0.229 Hom.: 1977

Bravo AF: 0.315

Asia WGS AF: 0.512 AC: 1783 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.12
DANN	Benign	0.35
PhyloP100		-6.1

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

Other links and lift over

dbSNP: rs2241894; hg19: chr4-100266133; COSMIC: COSV72463585;