4-99346892-T-G

Variant names:

• chr4-99346892-T-G
• rs1693431
• NM_000669.5:c.259+114A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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 (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 rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.259+114A>C		intron_variant	Intron 3 of 8	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.330+114A>C		intron_variant	Intron 3 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.259+114A>C		intron_variant	Intron 3 of 8	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.139+114A>C		intron_variant	Intron 4 of 6	3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.157+114A>C		intron_variant	Intron 2 of 4	3		ENSP00000478545.1
ADH1C	ENST00000505942.2	n.328+114A>C		intron_variant	Intron 3 of 4	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

African (AFR) AF: 0.133 AC: 3952 AN: 29684

American (AMR) AF: 0.325 AC: 9754 AN: 30046

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 5546 AN: 20116

East Asian (EAS) AF: 0.0642 AC: 2440 AN: 37978

South Asian (SAS) AF: 0.321 AC: 21928 AN: 68378

European-Finnish (FIN) AF: 0.516 AC: 25715 AN: 49868

Middle Eastern (MID) AF: 0.213 AC: 782 AN: 3670

European-Non Finnish (NFE) AF: 0.414 AC: 436327 AN: 1053742

Other (OTH) AF: 0.364 AC: 20212 AN: 55542

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

African (AFR) AF: 0.144 AC: 5959 AN: 41460

American (AMR) AF: 0.292 AC: 4468 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 945 AN: 3470

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

South Asian (SAS) AF: 0.296 AC: 1423 AN: 4812

European-Finnish (FIN) AF: 0.513 AC: 5407 AN: 10530

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

European-Non Finnish (NFE) AF: 0.412 AC: 27956 AN: 67922

Other (OTH) AF: 0.282 AC: 593 AN: 2106

Alfa AF: 0.364 Hom.: 1476

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
PhyloP100		-2.3

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