rs1693431

chr4-99346892-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000669.5(ADH1C):c.259+114A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,500,972 control chromosomes in the GnomAD database, including 117,181 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 (8843 hom., cov: 30)
  • Exomes 𝑓: 0.39 (108338 hom.)
• Consequence: ADH1C NM_000669.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• 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/exons	MANE	UniProt
ADH1C	NM_000669.5	c.259+114A>C		intron_variant		ENST00000515683.6
ADH1C	NR_133005.2	n.330+114A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH1C	ENST00000515683.6	c.259+114A>C		intron_variant		1	NM_000669.5	P1
ADH1C	ENST00000510055.5	c.139+114A>C		intron_variant		3
ADH1C	ENST00000511397.3	c.157+114A>C		intron_variant		3
ADH1C	ENST00000505942.2	n.328+114A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47424 AN: 151830 Hom.: 8837 Cov.: 30

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.228

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: 0.279

GnomAD4 exome AF: 0.390 AC: 526656 AN: 1349024 Hom.: 108338 AF XY: 0.387 AC XY: 256641 AN XY: 663020

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.325

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.0642

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.516

Gnomad4 NFE exome AF: 0.414

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.312 AC: 47445 AN: 151948 Hom.: 8843 Cov.: 30 AF XY: 0.313 AC XY: 23226 AN XY: 74274

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.0809

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.282

Alfa AF: 0.373 Hom.: 1464

Bravo AF: 0.287

Asia WGS AF: 0.220 AC: 763 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.85
Dann	Benign	0.64

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: rs1693431; hg19: chr4-100268049; COSMIC: COSV72463471;