4-99318162-T-C

Variant names:

• chr4-99318162-T-C
• rs1229984
• NM_000668.6:c.143A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000668.6(ADH1B):​c.143A>G​(p.His48Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.943 in 1,614,054 control chromosomes in the GnomAD database, including 730,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.94 (68555 hom., cov: 31)
  • Exomes 𝑓: 0.94 (661603 hom.)
• Consequence: ADH1B NM_000668.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2153893E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1B	NM_000668.6	c.143A>G	p.His48Arg	missense_variant	Exon 3 of 9	ENST00000305046.13	NP_000659.2
ADH1B	NM_001286650.2	c.23A>G	p.His8Arg	missense_variant	Exon 4 of 10		NP_001273579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1B	ENST00000305046.13	c.143A>G	p.His48Arg	missense_variant	Exon 3 of 9	1	NM_000668.6	ENSP00000306606.8

Frequencies

GnomAD3 genomes AF: 0.940 AC: 142955 AN: 152126 Hom.: 68493 Cov.: 31

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.932

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.885

GnomAD3 exomes AF: 0.900 AC: 226269 AN: 251392 Hom.: 106325 AF XY: 0.903 AC XY: 122683 AN XY: 135858

Gnomad AFR exome AF: 0.989

Gnomad AMR exome AF: 0.944

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.261

Gnomad SAS exome AF: 0.950

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.962

Gnomad OTH exome AF: 0.889

GnomAD4 exome AF: 0.943 AC: 1378462 AN: 1461810 Hom.: 661603 Cov.: 61 AF XY: 0.942 AC XY: 684937 AN XY: 727216

Gnomad4 AFR exome AF: 0.987

Gnomad4 AMR exome AF: 0.941

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.951

Gnomad4 FIN exome AF: 0.995

Gnomad4 NFE exome AF: 0.971

Gnomad4 OTH exome AF: 0.904

GnomAD4 genome AF: 0.940 AC: 143081 AN: 152244 Hom.: 68555 Cov.: 31 AF XY: 0.937 AC XY: 69757 AN XY: 74428

Gnomad4 AFR AF: 0.988

Gnomad4 AMR AF: 0.932

Gnomad4 ASJ AF: 0.731

Gnomad4 EAS AF: 0.296

Gnomad4 SAS AF: 0.959

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.964

Gnomad4 OTH AF: 0.884

Alfa AF: 0.951 Hom.: 27329

Bravo AF: 0.931

TwinsUK AF: 0.966 AC: 3583

ALSPAC AF: 0.969 AC: 3736

ESP6500AA AF: 0.984 AC: 4335

ESP6500EA AF: 0.953 AC: 8196

ExAC AF: 0.906 AC: 110036

Asia WGS AF: 0.762 AC: 2653 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.57
DEOGEN2	Benign	0.0052	.;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.37	.;T;.;T
MetaRNN	Benign	0.0000022	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.25	N;.;.;.
REVEL	Benign	0.090
Sift	Benign	0.77	T;.;.;.
Sift4G	Benign	0.25	T;T;T;.
Vest4		0.088
MPC		0.21
ClinPred		0.00059	T
GERP RS		3.6
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1229984; hg19: chr4-100239319; COSMIC: COSV59295640;