rs4147542

Variant names:

• chr4-99347396-T-C
• rs4147542
• NM_000669.5:c.121-252A>G

Variant summary

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

The NM_000669.5(ADH1C):​c.121-252A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 152,012 control chromosomes in the GnomAD database, including 9,897 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 0.34 (9897 hom., cov: 32)
• Consequence: ADH1C NM_000669.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0350
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.121-252A>G		intron_variant	Intron 2 of 8	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.192-252A>G		intron_variant	Intron 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.121-252A>G		intron_variant	Intron 2 of 8	1	NM_000669.5	ENSP00000426083.1
ADH1C	ENST00000510055.5	c.1-252A>G		intron_variant	Intron 3 of 6	3		ENSP00000478439.1
ADH1C	ENST00000511397.3	c.19-252A>G		intron_variant	Intron 1 of 4	3		ENSP00000478545.1
ADH1C	ENST00000505942.2	n.190-252A>G		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50906 AN: 151894 Hom.: 9897 Cov.: 32

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.335 AC: 50934 AN: 152012 Hom.: 9897 Cov.: 32 AF XY: 0.339 AC XY: 25203 AN XY: 74334

African (AFR) AF: 0.465 AC: 19243 AN: 41422

American (AMR) AF: 0.222 AC: 3391 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3468

East Asian (EAS) AF: 0.754 AC: 3905 AN: 5182

South Asian (SAS) AF: 0.549 AC: 2646 AN: 4820

European-Finnish (FIN) AF: 0.190 AC: 2009 AN: 10584

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.265 AC: 18006 AN: 67956

Other (OTH) AF: 0.308 AC: 647 AN: 2102

Alfa AF: 0.281 Hom.: 6941

Bravo AF: 0.336

Asia WGS AF: 0.515 AC: 1783 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.1
DANN	Benign	0.85
PhyloP100		-0.035

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: rs4147542; hg19: chr4-100268553;