4-99342785-C-T

Variant names:

• chr4-99342785-C-T
• rs1789912
• NM_000669.5:c.828+10G>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+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,610,930 control chromosomes in the GnomAD database, including 124,680 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 (8874 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115806 hom.)
• Consequence: ADH1C NM_000669.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 7 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.

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+10G>A		intron	N/A	NP_000660.1	P00326
	ADH1C	NR_133005.2		n.855+54G>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+10G>A		intron	N/A	ENSP00000426083.1	P00326
	ADH1C	ENST00000865215.1		c.828+10G>A		intron	N/A	ENSP00000535274.1
	ADH1C	ENST00000865216.1		c.828+10G>A		intron	N/A	ENSP00000535275.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47519 AN: 152046 Hom.: 8867 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.0819

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.514

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.281

GnomAD2 exomes AF: 0.345 AC: 86473 AN: 250590 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: 565492 AN: 1458766 Hom.: 115806 Cov.: 63 AF XY: 0.385 AC XY: 279105 AN XY: 725782

African (AFR) AF: 0.134 AC: 4473 AN: 33468

American (AMR) AF: 0.323 AC: 14432 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7110 AN: 26080

East Asian (EAS) AF: 0.0649 AC: 2578 AN: 39700

South Asian (SAS) AF: 0.321 AC: 27693 AN: 86206

European-Finnish (FIN) AF: 0.515 AC: 27502 AN: 53414

Middle Eastern (MID) AF: 0.269 AC: 1548 AN: 5762

European-Non Finnish (NFE) AF: 0.413 AC: 458491 AN: 1109118

Other (OTH) AF: 0.359 AC: 21665 AN: 60316

GnomAD4 genome AF: 0.312 AC: 47540 AN: 152164 Hom.: 8874 Cov.: 33 AF XY: 0.313 AC XY: 23290 AN XY: 74386

African (AFR) AF: 0.144 AC: 5973 AN: 41532

American (AMR) AF: 0.293 AC: 4474 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 945 AN: 3466

East Asian (EAS) AF: 0.0815 AC: 422 AN: 5180

South Asian (SAS) AF: 0.296 AC: 1430 AN: 4828

European-Finnish (FIN) AF: 0.514 AC: 5437 AN: 10580

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

European-Non Finnish (NFE) AF: 0.412 AC: 27982 AN: 67988

Other (OTH) AF: 0.284 AC: 599 AN: 2110

Alfa AF: 0.352 Hom.: 7163

Bravo AF: 0.287

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.68
DANN	Benign	0.62
PhyloP100		-1.5

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: rs1789912; hg19: chr4-100263942; COSMIC: COSV72463408; COSMIC: COSV72463408;