Variant 4-99210500-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001102470.2(ADH6):c.265G>A(p.Asp89Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,454,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADH6
NM_001102470.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53

Variant links:

Genes affected

ADH6 (HGNC:255): (alcohol dehydrogenase 6 (class V)) This gene encodes class V alcohol dehydrogenase, 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. This gene is expressed in the stomach as well as in the liver, and it contains a glucocorticoid response element upstream of its 5' UTR, which is a steroid hormone receptor binding site. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ADH6 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADH6	NM_001102470.2 linkuse as main transcript	c.265G>A	p.Asp89Asn	missense_variant, splice_region_variant	4/9	ENST00000394899.6
LOC100507053	NR_037884.1 linkuse as main transcript	n.3789+6069C>T		intron_variant, non_coding_transcript_variant
ADH6	NM_000672.4 linkuse as main transcript	c.265G>A	p.Asp89Asn	missense_variant, splice_region_variant	4/8
ADH6	NR_132990.2 linkuse as main transcript	n.217G>A		splice_region_variant, non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH6	ENST00000394899.6 linkuse as main transcript	c.265G>A	p.Asp89Asn	missense_variant, splice_region_variant	4/9	2	NM_001102470.2	P1	P28332-2
	ENST00000500358.6 linkuse as main transcript	n.3789+6069C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723862

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000451

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Mar 12, 2024

The c.265G>A (p.D89N) alteration is located in exon 4 (coding exon 4) of the ADH6 gene. This alteration results from a G to A substitution at nucleotide position 265, causing the aspartic acid (D) at amino acid position 89 to be replaced by an asparagine (N). 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

Uncertain

0.44

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

.;.;T

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Benign

-0.60

MutationAssessor

Pathogenic

3.7

.;H;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.76

MutPred

0.87

Gain of catalytic residue at D89 (P = 0.0143);Gain of catalytic residue at D89 (P = 0.0143);Gain of catalytic residue at D89 (P = 0.0143);

MVP

0.83

MPC

0.49

ClinPred

1.0

GERP RS

4.4

Varity_R

0.84

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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