chr4-99345000-G-A

Position:

• chr4-99345000-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000669.5(ADH1C):​c.429C>T​(p.Gly143=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,614,148 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: ADH1C NM_000669.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.642

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-99345000-G-A is Benign according to our data. Variant chr4-99345000-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 716191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.642 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.429C>T	p.Gly143=	synonymous_variant	5/9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.500C>T		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.429C>T	p.Gly143=	synonymous_variant	5/9	1	NM_000669.5	ENSP00000426083	P1
ADH1C	ENST00000510055.5	c.309C>T	p.Gly103=	synonymous_variant	6/7	3		ENSP00000478439
ADH1C	ENST00000511397.3	c.327C>T	p.Gly109=	synonymous_variant	4/5	3		ENSP00000478545
ADH1C	ENST00000505942.2	n.452C>T		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00186 AC: 468 AN: 251370 Hom.: 1 AF XY: 0.00175 AC XY: 238 AN XY: 135866

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00642

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00196 AC: 2859 AN: 1461884 Hom.: 6 Cov.: 38 AF XY: 0.00189 AC XY: 1371 AN XY: 727244

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.00723

Gnomad4 NFE exome AF: 0.00203

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74458

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00584

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	ADH1C: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.8
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs79372027; hg19: chr4-100266157;