Variant 4-99342945-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.84

Variant links:

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]

ADH1C links:

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ACMG classification

Classification made for transcript

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 GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH1C	NM_000669.5 linkuse as main transcript	c.678C>T	p.Asn226=	synonymous_variant	6/9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2 linkuse as main transcript	n.749C>T		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6 linkuse as main transcript	c.678C>T	p.Asn226=	synonymous_variant	6/9	1	NM_000669.5	ENSP00000426083	P1
ADH1C	ENST00000510055.5 linkuse as main transcript	c.558C>T	p.Asn186=	synonymous_variant	7/7	3		ENSP00000478439

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1554

AN:

152134

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0123

AC XY:

1668

AN XY:

135904

show subpopulations

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.:

AF XY:

0.0144

AC XY:

10443

AN XY:

727242

show subpopulations

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.:

Cov.:

AF XY:

0.0104

AC XY:

771

AN XY:

74436

show subpopulations

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.:

Bravo

AF:

0.00889

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over