Variant 4-99339626-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000669.5(ADH1C):c.1054C>A(p.Pro352Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00416 in 1,606,172 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0052 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 81 hom. )

Consequence

ADH1C
NM_000669.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.92

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046266615).

BP6

Variant 4-99339626-G-T is Benign according to our data. Variant chr4-99339626-G-T is described in ClinVar as [Benign]. Clinvar id is 778860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00525 (796/151720) while in subpopulation AMR AF= 0.0311 (472/15190). AF 95% confidence interval is 0.0288. There are 8 homozygotes in gnomad4. There are 388 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH1C	NM_000669.5 link	c.1054C>A	p.Pro352Thr	missense_variant	8/9	ENST00000515683.6	NP_000660.1	P00326
ADH1C	NR_133005.2 link	n.1081C>A		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6 link	c.1054C>A	p.Pro352Thr	missense_variant	8/9	1	NM_000669.5	ENSP00000426083.1		P00326

Frequencies

GnomAD3 genomes

AF:

0.00521

AC:

790

AN:

151602

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000703

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0308

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00602

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00285

Gnomad OTH

AF:

0.00814

GnomAD3 exomes

AF:

0.00959

AC:

2376

AN:

247630

Hom.:

AF XY:

0.00775

AC XY:

1039

AN XY:

134130

show subpopulations

Gnomad AFR exome

AF:

0.000707

Gnomad AMR exome

AF:

0.0522

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00327

Gnomad FIN exome

AF:

0.00671

Gnomad NFE exome

AF:

0.00255

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.00405

AC:

5885

AN:

1454452

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

2750

AN XY:

723440

show subpopulations

Gnomad4 AFR exome

AF:

0.000604

Gnomad4 AMR exome

AF:

0.0517

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00355

Gnomad4 FIN exome

AF:

0.00759

Gnomad4 NFE exome

AF:

0.00238

Gnomad4 OTH exome

AF:

0.00406

GnomAD4 genome

AF:

0.00525

AC:

796

AN:

151720

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

388

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.000701

Gnomad4 AMR

AF:

0.0311

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00602

Gnomad4 NFE

AF:

0.00285

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00264

Hom.:

Bravo

AF:

0.00890

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00230

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00799

AC:

969

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0046

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.52

Sift4G

Benign

0.15

Polyphen

0.089

Vest4

0.20

MVP

0.55

GERP RS

3.0

Varity_R

0.33

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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