Genetic Variant ADH1C:c.828+118G>A (chr4-99342677-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000669.5(ADH1C):c.828+118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,474,036 control chromosomes in the GnomAD database, including 111,857 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 8857 hom., cov: 32)

Exomes 𝑓: 0.38 ( 103000 hom. )

Consequence

ADH1C
NM_000669.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.140

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5 link	c.828+118G>A		intron_variant	Intron 6 of 8	ENST00000515683.6	NP_000660.1	P00326
ADH1C	NR_133005.2 link	n.855+162G>A		intron_variant	Intron 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6 link	c.828+118G>A		intron_variant	Intron 6 of 8	1	NM_000669.5	ENSP00000426083.1		P00326
ADH1C	ENST00000510055.5 link	c.*249G>A		downstream_gene_variant		3		ENSP00000478439.1		A0A087WU81

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

47476

AN:

151864

Hom.:

8850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.293

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.0813

Gnomad SAS

AF:

0.296

Gnomad FIN

AF:

0.514

Gnomad MID

AF:

0.252

Gnomad NFE

AF:

0.412

Gnomad OTH

AF:

0.279

GnomAD4 exome

AF:

0.384

AC:

507901

AN:

1322054

Hom.:

103000

AF XY:

0.381

AC XY:

248411

AN XY:

651582

show subpopulations

African (AFR)

AF:

0.131

AC:

3921

AN:

29912

American (AMR)

AF:

0.317

AC:

10364

AN:

32722

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

5588

AN:

20556

East Asian (EAS)

AF:

0.0650

AC:

2516

AN:

38706

South Asian (SAS)

AF:

0.316

AC:

22062

AN:

69820

European-Finnish (FIN)

AF:

0.515

AC:

25755

AN:

50042

Middle Eastern (MID)

AF:

0.271

AC:

1429

AN:

5270

European-Non Finnish (NFE)

AF:

0.408

AC:

416563

AN:

1020076

Other (OTH)

AF:

0.359

AC:

19703

AN:

54950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

13752

27503

41255

55006

68758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12716

25432

38148

50864

63580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.313

AC:

47497

AN:

151982

Hom.:

8857

Cov.:

AF XY:

0.313

AC XY:

23250

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.144

AC:

5959

AN:

41472

American (AMR)

AF:

0.293

AC:

4475

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

945

AN:

3470

East Asian (EAS)

AF:

0.0809

AC:

419

AN:

5180

South Asian (SAS)

AF:

0.297

AC:

1429

AN:

4818

European-Finnish (FIN)

AF:

0.514

AC:

5415

AN:

10528

Middle Eastern (MID)

AF:

0.240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.412

AC:

27980

AN:

67946

Other (OTH)

AF:

0.282

AC:

596

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1533

3065

4598

6130

7663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.358

Hom.:

1423

Bravo

AF:

0.287

Asia WGS

AF:

0.221

AC:

765

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.8

(source)

DANN

Benign

0.43

PhyloP100

0.14

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over