4-99315975-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000668.6(ADH1B):c.490G>T(p.Ala164Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADH1B NM_000668.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.530

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13103655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH1B	NM_000668.6	c.490G>T	p.Ala164Ser	missense_variant	5/9	ENST00000305046.13
ADH1B	NM_001286650.2	c.370G>T	p.Ala124Ser	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH1B	ENST00000305046.13	c.490G>T	p.Ala164Ser	missense_variant	5/9	1	NM_000668.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Oct 26, 2022

The c.490G>T (p.A164S) alteration is located in exon 5 (coding exon 5) of the ADH1B gene. This alteration results from a G to T substitution at nucleotide position 490, causing the alanine (A) at amino acid position 164 to be replaced by a serine (S). 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	0.076
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	16
Dann	Benign	0.87
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.099	N
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.76	N;.;.;.
REVEL	Benign	0.047
Sift	Benign	0.30	T;.;.;.
Sift4G	Benign	0.71	T;T;T;.
Vest4		0.22
MutPred		0.25		Gain of disorder (P = 0.0551);.;.;Gain of disorder (P = 0.0551);
MVP		0.15
MPC		0.16
ClinPred		0.084	T
GERP RS		3.0
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100237132;