dbSNP rs376943095: ADH4:p.Pro87Leu (chr4-99141543-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000670.5(ADH4):c.260C>T(p.Pro87Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,452,424 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P87R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ADH4
NM_000670.5 missense, splice_region

Scores

Splicing: ADA: 0.9091

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.76

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH4	NM_000670.5 link	c.260C>T	p.Pro87Leu	missense_variant, splice_region_variant	Exon 3 of 9	ENST00000265512.12	NP_000661.2	P08319-1V9HVX7
ADH4	NM_001306171.2 link	c.317C>T	p.Pro106Leu	missense_variant, splice_region_variant	Exon 4 of 10		NP_001293100.1	P08319-2V9HVX7
ADH4	NM_001306172.2 link	c.317C>T	p.Pro106Leu	missense_variant, splice_region_variant	Exon 4 of 10		NP_001293101.1	P08319-2V9HVX7
LOC100507053	NR_037884.1 link	n.679+7738G>A		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12 link	c.260C>T	p.Pro87Leu	missense_variant, splice_region_variant	Exon 3 of 9	1	NM_000670.5	ENSP00000265512.7		P08319-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452424

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722362

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:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.0022

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.081

.;T;T;.;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

.;D;D;D;D;D

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.63

D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;.;L;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-7.4

D;.;D;D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0040

D;.;D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;D;.;.

Polyphen

0.89

P;.;D;P;.;.

Vest4

0.61

MutPred

0.55

.;Loss of disorder (P = 0.045);Loss of disorder (P = 0.045);.;.;Loss of disorder (P = 0.045);

MVP

0.53

MPC

0.28

ClinPred

1.0

GERP RS

3.6

Varity_R

0.65

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.67

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over