4-99342677-C-T

Variant names:

• chr4-99342677-C-T
• rs1693481
• NM_000669.5:c.828+118G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000669.5(ADH1C):​c.828+118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,474,036 control chromosomes in the GnomAD database, including 111,857 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: 0.38 (103000 hom.)
• Consequence: ADH1C NM_000669.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140
• 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=-0.9).
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	NM_000669.5	MANE Select	c.828+118G>A		intron	N/A	NP_000660.1
	ADH1C	NR_133005.2		n.855+162G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1C	ENST00000515683.6	TSL:1 MANE Select	c.828+118G>A		intron	N/A	ENSP00000426083.1
	ADH1C	ENST00000865215.1		c.828+118G>A		intron	N/A	ENSP00000535274.1
	ADH1C	ENST00000865216.1		c.828+118G>A		intron	N/A	ENSP00000535275.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47476 AN: 151864 Hom.: 8850 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0813

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.384 AC: 507901 AN: 1322054 Hom.: 103000 AF XY: 0.381 AC XY: 248411 AN XY: 651582

African (AFR) AF: 0.131 AC: 3921 AN: 29912

American (AMR) AF: 0.317 AC: 10364 AN: 32722

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 5588 AN: 20556

East Asian (EAS) AF: 0.0650 AC: 2516 AN: 38706

South Asian (SAS) AF: 0.316 AC: 22062 AN: 69820

European-Finnish (FIN) AF: 0.515 AC: 25755 AN: 50042

Middle Eastern (MID) AF: 0.271 AC: 1429 AN: 5270

European-Non Finnish (NFE) AF: 0.408 AC: 416563 AN: 1020076

Other (OTH) AF: 0.359 AC: 19703 AN: 54950

GnomAD4 genome AF: 0.313 AC: 47497 AN: 151982 Hom.: 8857 Cov.: 32 AF XY: 0.313 AC XY: 23250 AN XY: 74268

African (AFR) AF: 0.144 AC: 5959 AN: 41472

American (AMR) AF: 0.293 AC: 4475 AN: 15256

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

East Asian (EAS) AF: 0.0809 AC: 419 AN: 5180

South Asian (SAS) AF: 0.297 AC: 1429 AN: 4818

European-Finnish (FIN) AF: 0.514 AC: 5415 AN: 10528

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.412 AC: 27980 AN: 67946

Other (OTH) AF: 0.282 AC: 596 AN: 2110

Alfa AF: 0.358 Hom.: 1423

Bravo AF: 0.287

Asia WGS AF: 0.221 AC: 765 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.8
DANN	Benign	0.43
PhyloP100		0.14

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: rs1693481; hg19: chr4-100263834; COSMIC: COSV72463407; COSMIC: COSV72463407;