Genetic Variant ADH7:p.Arg218Ser (chr4-99420704-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000673.7(ADH7):c.654G>C(p.Arg218Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADH7
NM_000673.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.672

Publications

0 publications found

Variant links:

Genes affected

ADH7 (HGNC:256): (alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide) This gene encodes class IV alcohol dehydrogenase 7 mu or sigma subunit, which is a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. The enzyme encoded by this gene is inefficient in ethanol oxidation, but is the most active as a retinol dehydrogenase; thus it may participate in the synthesis of retinoic acid, a hormone important for cellular differentiation. The expression of this gene is much more abundant in stomach than liver, thus differing from the other known gene family members. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ADH7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH7	NM_000673.7 link	c.654G>C	p.Arg218Ser	missense_variant	Exon 6 of 9	ENST00000437033.7	NP_000664.3
ADH7	NM_001166504.2 link	c.714G>C	p.Arg238Ser	missense_variant	Exon 6 of 9		NP_001159976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ADH7	ENST00000437033.7 link	c.654G>C	p.Arg218Ser	missense_variant	Exon 6 of 9	1	NM_000673.7	ENSP00000414254.2
ADH7	ENST00000209665.8 link	c.690G>C	p.Arg230Ser	missense_variant	Exon 6 of 9	1		ENSP00000209665.4
ADH7	ENST00000476959.5 link	c.714G>C	p.Arg238Ser	missense_variant	Exon 6 of 9	2		ENSP00000420269.1
ADH7	ENST00000482593.5 link	c.483G>C	p.Arg161Ser	missense_variant	Exon 7 of 10	3		ENSP00000420613.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111914

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

0.0023

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.0093

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.2

M;.;.;.

PhyloP100

0.67

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.5

D;D;D;D

REVEL

Benign

0.22

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.72

MutPred

0.79

Gain of phosphorylation at R230 (P = 0.0485);.;.;.;

MVP

0.55

MPC

0.17

ClinPred

1.0

GERP RS

1.1

Varity_R

0.94

gMVP

0.64

Mutation Taster

=65/35

polymorphism

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over