4-99318127-T-G

Position:

• chr4-99318127-T-G

Variant summary

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

The NM_000668.6(ADH1B):​c.178A>C​(p.Thr60Pro) 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. 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. T60S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADH1B NM_000668.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.83

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=0.120373905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH1B	NM_000668.6	c.178A>C	p.Thr60Pro	missense_variant	3/9	ENST00000305046.13
ADH1B	NM_001286650.2	c.58A>C	p.Thr20Pro	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH1B	ENST00000305046.13	c.178A>C	p.Thr60Pro	missense_variant	3/9	1	NM_000668.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.021
DANN	Benign	0.63
DEOGEN2	Benign	0.016	.;T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.66	.;T;.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N;.;.;.
REVEL	Benign	0.065
Sift	Benign	0.25	T;.;.;.
Sift4G	Benign	0.085	T;T;T;.
Vest4		0.18
MutPred		0.25		Loss of glycosylation at T60 (P = 0.0394);.;.;Loss of glycosylation at T60 (P = 0.0394);
MVP		0.11
MPC		0.36
ClinPred		0.20	T
GERP RS		-8.8
gMVP		0.51

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

Other links and lift over

dbSNP: rs6413413; hg19: chr4-100239284;