4-99347033-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BA1

The NM_000669.5(ADH1C):c.232G>T(p.Gly78Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0124 in 1,614,018 control chromosomes in the GnomAD database, including 326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.013 (310 hom.)
• Consequence: ADH1C NM_000669.5 stop_gained
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 7.18

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM4: Stoplost variant in NM_000669.5 Downstream stopcodon found after 16 codons.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH1C	NM_000669.5	c.232G>T	p.Gly78Ter	stop_gained	3/9	ENST00000515683.6
ADH1C	NR_133005.2	n.303G>T		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH1C	ENST00000515683.6	c.232G>T	p.Gly78Ter	stop_gained	3/9	1	NM_000669.5	P1
ADH1C	ENST00000510055.5	c.112G>T	p.Gly38Ter	stop_gained	4/7	3
ADH1C	ENST00000511397.3	c.130G>T	p.Gly44Ter	stop_gained	2/5	3
ADH1C	ENST00000505942.2	n.301G>T		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1573 AN: 152100 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0316

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0249

GnomAD4 exome AF: 0.0126 AC: 18384 AN: 1461800 Hom.: 310 Cov.: 32 AF XY: 0.0138 AC XY: 10056 AN XY: 727192

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.0609

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0390

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00992

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0104 AC: 1576 AN: 152218 Hom.: 16 Cov.: 32 AF XY: 0.0105 AC XY: 778 AN XY: 74410

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0674

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0320

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0125 Hom.: 17

Bravo AF: 0.0105

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Parkinson disease, mitochondrial Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Pathogenic	41
Vest4		0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs283413; hg19: chr4-100268190;