chr4-99344955-C-T

Variant names:

• chr4-99344955-C-T
• rs1693425
• NM_000669.5:c.474G>A

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.474G>A​(p.Val158Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,613,934 control chromosomes in the GnomAD database, including 124,699 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 (8857 hom., cov: 32)
  • Exomes 𝑓: 0.39 (115842 hom.)
• Consequence: ADH1C NM_000669.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.860
• Publications: 18 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=-0.49).
• BP7: Synonymous conserved (PhyloP=-0.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	NM_000669.5	MANE Select	c.474G>A	p.Val158Val	synonymous	Exon 5 of 9	NP_000660.1
	ADH1C	NR_133005.2		n.545G>A		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	ENST00000515683.6	TSL:1 MANE Select	c.474G>A	p.Val158Val	synonymous	Exon 5 of 9	ENSP00000426083.1
	ADH1C	ENST00000510055.5	TSL:3	c.354G>A	p.Val118Val	synonymous	Exon 6 of 7	ENSP00000478439.1
	ADH1C	ENST00000511397.3	TSL:3	c.372G>A	p.Val124Val	synonymous	Exon 4 of 5	ENSP00000478545.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47467 AN: 151956 Hom.: 8851 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0813

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.345 AC: 86817 AN: 251430 AF XY: 0.349

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.0781

Gnomad FIN exome AF: 0.517

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.347

GnomAD4 exome AF: 0.388 AC: 567064 AN: 1461860 Hom.: 115842 Cov.: 79 AF XY: 0.385 AC XY: 279839 AN XY: 727232

African (AFR) AF: 0.134 AC: 4485 AN: 33480

American (AMR) AF: 0.323 AC: 14432 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7136 AN: 26136

East Asian (EAS) AF: 0.0649 AC: 2577 AN: 39700

South Asian (SAS) AF: 0.321 AC: 27716 AN: 86254

European-Finnish (FIN) AF: 0.515 AC: 27505 AN: 53420

Middle Eastern (MID) AF: 0.269 AC: 1551 AN: 5768

European-Non Finnish (NFE) AF: 0.414 AC: 459951 AN: 1111984

Other (OTH) AF: 0.359 AC: 21711 AN: 60396

GnomAD4 genome AF: 0.312 AC: 47488 AN: 152074 Hom.: 8857 Cov.: 32 AF XY: 0.313 AC XY: 23247 AN XY: 74330

African (AFR) AF: 0.144 AC: 5971 AN: 41518

American (AMR) AF: 0.292 AC: 4462 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3468

East Asian (EAS) AF: 0.0809 AC: 418 AN: 5166

South Asian (SAS) AF: 0.296 AC: 1425 AN: 4808

European-Finnish (FIN) AF: 0.513 AC: 5417 AN: 10560

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

European-Non Finnish (NFE) AF: 0.412 AC: 27983 AN: 67974

Other (OTH) AF: 0.281 AC: 591 AN: 2104

Alfa AF: 0.359 Hom.: 4683

Bravo AF: 0.287

Asia WGS AF: 0.220 AC: 764 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.8
DANN	Benign	0.50
PhyloP100		-0.86

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: rs1693425; hg19: chr4-100266112; COSMIC: COSV72463410;