4-99336998-C-T

Variant names:

• chr4-99336998-C-T
• rs1614972
• NM_000669.5:c.1104-222G>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.1104-222G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 152,004 control chromosomes in the GnomAD database, including 12,338 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 0.38 (12338 hom., cov: 32)
• Consequence: ADH1C NM_000669.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• Publications: 42 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.733 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.1104-222G>A		intron	N/A	NP_000660.1	P00326
	ADH1C	NR_133005.2		n.1131-222G>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.1104-222G>A		intron	N/A	ENSP00000426083.1	P00326
	ADH1C	ENST00000865215.1		c.1104-222G>A		intron	N/A	ENSP00000535274.1
	ADH1C	ENST00000865216.1		c.1104-222G>A		intron	N/A	ENSP00000535275.1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57561 AN: 151886 Hom.: 12330 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.367

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.379 AC: 57602 AN: 152004 Hom.: 12338 Cov.: 32 AF XY: 0.383 AC XY: 28427 AN XY: 74276

African (AFR) AF: 0.526 AC: 21801 AN: 41470

American (AMR) AF: 0.276 AC: 4217 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3470

East Asian (EAS) AF: 0.753 AC: 3891 AN: 5166

South Asian (SAS) AF: 0.554 AC: 2675 AN: 4828

European-Finnish (FIN) AF: 0.265 AC: 2803 AN: 10564

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19898 AN: 67928

Other (OTH) AF: 0.363 AC: 767 AN: 2112

Alfa AF: 0.329 Hom.: 12018

Bravo AF: 0.382

Asia WGS AF: 0.532 AC: 1853 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.58
PhyloP100		-0.38

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: rs1614972; hg19: chr4-100258155;