4-99342945-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000669.5(ADH1C):c.678C>T(p.Asn226=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,132 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.015 (195 hom.)
• Consequence: ADH1C NM_000669.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-99342945-G-A is Benign according to our data. Variant chr4-99342945-G-A is described in ClinVar as [Benign]. Clinvar id is 2654966.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0145 (21234/1461880) while in subpopulation NFE AF= 0.0156 (17308/1112008). AF 95% confidence interval is 0.0154. There are 195 homozygotes in gnomad4_exome. There are 10443 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH1C	NM_000669.5	c.678C>T	p.Asn226=	synonymous_variant	6/9	ENST00000515683.6
ADH1C	NR_133005.2	n.749C>T		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH1C	ENST00000515683.6	c.678C>T	p.Asn226=	synonymous_variant	6/9	1	NM_000669.5	P1
ADH1C	ENST00000510055.5	c.558C>T	p.Asn186=	synonymous_variant	7/7	3

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1554 AN: 152134 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0118 AC: 2970 AN: 251460 Hom.: 28 AF XY: 0.0123 AC XY: 1668 AN XY: 135904

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00671

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0145 AC: 21234 AN: 1461880 Hom.: 195 Cov.: 33 AF XY: 0.0144 AC XY: 10443 AN XY: 727242

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00749

Gnomad4 ASJ exome AF: 0.0249

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0102 AC: 1555 AN: 152252 Hom.: 14 Cov.: 32 AF XY: 0.0104 AC XY: 771 AN XY: 74436

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00748

Gnomad4 FIN AF: 0.0205

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.0148 Hom.: 6

Bravo AF: 0.00889

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

ADH1C: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	6.6
Dann	Benign	0.52

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: rs6413444; hg19: chr4-100264102;