4-99085165-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000671.4(ADH5):c.64A>G(p.Ile22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000309 in 1,554,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

ADH5
NM_000671.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Variant links:

Genes affected

ADH5 (HGNC:253): (alcohol dehydrogenase 5 (class III), chi polypeptide) This gene encodes 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 encoded protein forms a homodimer. It has virtually no activity for ethanol oxidation, but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione. This enzyme is an important component of cellular metabolism for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes lacrymation, rhinitis, pharyngitis, and contact dermatitis. The human genome contains several non-transcribed pseudogenes related to this gene. [provided by RefSeq, Oct 2008]

ADH5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1330533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH5	NM_000671.4 linkuse as main transcript	c.64A>G	p.Ile22Val	missense_variant	2/9	ENST00000296412.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH5	ENST00000296412.14 linkuse as main transcript	c.64A>G	p.Ile22Val	missense_variant	2/9	1	NM_000671.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

188268

Hom.:

AF XY:

0.0000198

AC XY:

AN XY:

100820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000519

Gnomad NFE exome

AF:

0.0000236

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1402368

Hom.:

Cov.:

AF XY:

0.0000360

AC XY:

AN XY:

693534

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000131

Gnomad4 FIN exome

AF:

0.0000776

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000863

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

The c.64A>G (p.I22V) alteration is located in exon 2 (coding exon 2) of the ADH5 gene. This alteration results from a A to G substitution at nucleotide position 64, causing the isoleucine (I) at amino acid position 22 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.11

T;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0088

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.3

L;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.81

N;.;N

REVEL

Benign

0.12

Sift

Benign

0.17

T;.;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.22

MutPred

0.48

Gain of ubiquitination at K18 (P = 0.0882);Gain of ubiquitination at K18 (P = 0.0882);.;

MVP

0.15

MPC

0.22

ClinPred

0.049

GERP RS

4.0

Varity_R

0.16

gMVP

0.60

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