rs35719513

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★).

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

Publications

14 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6 link	c.1054C>A	p.Pro352Thr	missense_variant	Exon 8 of 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

GnomAD2 exomes

AF:

0.00959

AC:

2376

AN:

247630

AF XY:

0.00775

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 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

African (AFR)

AF:

0.000604

AC:

AN:

33094

American (AMR)

AF:

0.0517

AC:

2268

AN:

43852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25928

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39532

South Asian (SAS)

AF:

0.00355

AC:

302

AN:

85188

European-Finnish (FIN)

AF:

0.00759

AC:

401

AN:

52820

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00238

AC:

2643

AN:

1108284

Other (OTH)

AF:

0.00406

AC:

244

AN:

60036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

243

486

729

972

1215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00525

AC:

796

AN:

151720

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

388

AN XY:

74108

show subpopulations

African (AFR)

AF:

0.000701

AC:

AN:

41346

American (AMR)

AF:

0.0311

AC:

472

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00415

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00602

AC:

AN:

10464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00285

AC:

194

AN:

67964

Other (OTH)

AF:

0.00806

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00337

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

3.9

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

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rs35719513

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over