Variant 4-99131683-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000670.5(ADH4):c.664G>A(p.Ala222Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000607 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

ADH4
NM_000670.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.94

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADH4	NM_000670.5 linkuse as main transcript	c.664G>A	p.Ala222Thr	missense_variant	6/9	ENST00000265512.12
LOC100507053	NR_037884.1 linkuse as main transcript	n.429-1872C>T		intron_variant, non_coding_transcript_variant
ADH4	NM_001306171.2 linkuse as main transcript	c.721G>A	p.Ala241Thr	missense_variant	7/10
ADH4	NM_001306172.2 linkuse as main transcript	c.721G>A	p.Ala241Thr	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH4	ENST00000265512.12 linkuse as main transcript	c.664G>A	p.Ala222Thr	missense_variant	6/9	1	NM_000670.5	P1	P08319-1
	ENST00000500358.6 linkuse as main transcript	n.429-1872C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251354

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135844

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:

0.000751

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

727242

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:

0.00107

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000741

AC:

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

Aug 22, 2023

The c.664G>A (p.A222T) alteration is located in exon 6 (coding exon 6) of the ADH4 gene. This alteration results from a G to A substitution at nucleotide position 664, causing the alanine (A) at amino acid position 222 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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D

MetaSVM

Uncertain

0.18

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.9

D;.;D;D;D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;.;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;.;.

Polyphen

1.0

D;.;D;D;.;.

Vest4

0.79

MutPred

0.86

.;Loss of ubiquitination at K218 (P = 0.1037);Loss of ubiquitination at K218 (P = 0.1037);.;.;.;

MVP

0.72

MPC

0.28

ClinPred

0.98

GERP RS

4.4

Varity_R

0.96

gMVP

0.69

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