4-99311614-C-A

Position:

• chr4-99311614-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000668.6(ADH1B):​c.871G>T​(p.Val291Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,744 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ADH1B NM_000668.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29

Genes affected

ADH1B (HGNC:250): (alcohol dehydrogenase 1B (class I), beta polypeptide) The protein encoded by this gene 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. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH1B	NM_000668.6	c.871G>T	p.Val291Phe	missense_variant	7/9	ENST00000305046.13
ADH1B	NM_001286650.2	c.751G>T	p.Val251Phe	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH1B	ENST00000305046.13	c.871G>T	p.Val291Phe	missense_variant	7/9	1	NM_000668.6	P1
ADH1B	ENST00000625860.2	c.751G>T	p.Val251Phe	missense_variant	7/9	1
ADH1B	ENST00000506651.5	c.751G>T	p.Val251Phe	missense_variant	8/10	2
ADH1B	ENST00000515694.4	n.2966G>T		non_coding_transcript_exon_variant	7/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727184

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.871G>T (p.V291F) alteration is located in exon 7 (coding exon 7) of the ADH1B gene. This alteration results from a G to T substitution at nucleotide position 871, causing the valine (V) at amino acid position 291 to be replaced by a phenylalanine (F). 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	0.74
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	.;T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.6	D;.;.;.
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;.
Vest4		0.90
MutPred		0.61		Loss of glycosylation at P296 (P = 0.0743);.;.;Loss of glycosylation at P296 (P = 0.0743);
MVP		0.57
MPC		0.78
ClinPred		1.0	D
GERP RS		3.7
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100232771;