4-99344976-T-C

Position:

• chr4-99344976-T-C

Variant summary

Our verdict is Benign. Variant got -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

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=-0.96).
• 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/exons	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.453A>G	p.Thr151Thr	synonymous_variant	5/9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.524A>G		non_coding_transcript_exon_variant	5/9

Ensembl

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

GnomAD3 exomes AF: 0.297 AC: 74637 AN: 251412 Hom.: 15193 AF XY: 0.306 AC XY: 41564 AN XY: 135884

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 SAS exome AF: 0.503

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

Gnomad4 AFR exome AF: 0.472

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.823

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.168

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.261

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

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.754

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.289

Alfa AF: 0.226 Hom.: 1892

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

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