chr4-99127320-C-T

Position:

chr4-99127320-C-T

Variant summary

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

The NM_000670.5(ADH4):c.868G>A(p.Ala290Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000077 in 1,611,328 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

ADH4
NM_000670.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.906

Variant links:

Genes affected

ADH4 (HGNC:252): (alcohol dehydrogenase 4 (class II), pi polypeptide) This gene encodes class II alcohol dehydrogenase 4 pi 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 II alcohol dehydrogenase is a homodimer composed of 2 pi subunits. It exhibits a high activity for oxidation of long-chain aliphatic alcohols and aromatic alcohols and is less sensitive to pyrazole. This gene is localized to chromosome 4 in the cluster of alcohol dehydrogenase genes. [provided by RefSeq, Jul 2008]

ADH4 links:

ENSG00000246090 (HGNC:):

ENSG00000246090 links:

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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=0.070982665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH4	NM_000670.5 linkuse as main transcript	c.868G>A	p.Ala290Thr	missense_variant	7/9	ENST00000265512.12	NP_000661.2	P08319-1V9HVX7
ADH4	NM_001306171.2 linkuse as main transcript	c.925G>A	p.Ala309Thr	missense_variant	8/10		NP_001293100.1	P08319-2V9HVX7
ADH4	NM_001306172.2 linkuse as main transcript	c.925G>A	p.Ala309Thr	missense_variant	8/10		NP_001293101.1	P08319-2V9HVX7
LOC100507053	NR_037884.1 linkuse as main transcript	n.429-6235C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12 linkuse as main transcript	c.868G>A	p.Ala290Thr	missense_variant	7/9	1	NM_000670.5	ENSP00000265512.7		P08319-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000881

AC:

AN:

249638

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

134990

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000816

AC:

119

AN:

1459110

Hom.:

Cov.:

AF XY:

0.0000909

AC XY:

AN XY:

725916

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.000291

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000702

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000444

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000110

EpiControl

AF:

0.0000596

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

Aug 20, 2024

The c.868G>A (p.A290T) alteration is located in exon 7 (coding exon 7) of the ADH4 gene. This alteration results from a G to A substitution at nucleotide position 868, causing the alanine (A) at amino acid position 290 to be replaced by a threonine (T). 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

0.090

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.72

DANN

Benign

0.84

DEOGEN2

Benign

0.015

.;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0072

LIST_S2

Benign

0.63

.;T;T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.071

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

.;.;L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.25

N;.;N;N

REVEL

Benign

0.022

Sift

Benign

0.14

T;.;T;T

Sift4G

Benign

0.072

T;T;T;T

Polyphen

0.69

P;.;B;P

Vest4

0.13

MutPred

0.27

.;Gain of glycosylation at T289 (P = 0.1567);Gain of glycosylation at T289 (P = 0.1567);.;

MVP

0.16

MPC

0.051

ClinPred

0.013

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.094

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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