4-99318162-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 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. H48N) has been classified as Uncertain significance.

• 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
• Publications: 824 publications found

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

Our verdict: Benign. The variant received -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

GnomAD2 exomes AF: 0.900 AC: 226269 AN: 251392 AF XY: 0.903

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 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

African (AFR) AF: 0.987 AC: 33042 AN: 33470

American (AMR) AF: 0.941 AC: 42088 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 19234 AN: 26136

East Asian (EAS) AF: 0.251 AC: 9973 AN: 39690

South Asian (SAS) AF: 0.951 AC: 82002 AN: 86256

European-Finnish (FIN) AF: 0.995 AC: 53172 AN: 53418

Middle Eastern (MID) AF: 0.786 AC: 4531 AN: 5766

European-Non Finnish (NFE) AF: 0.971 AC: 1079842 AN: 1111962

Other (OTH) AF: 0.904 AC: 54578 AN: 60394

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

African (AFR) AF: 0.988 AC: 41031 AN: 41534

American (AMR) AF: 0.932 AC: 14240 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 2539 AN: 3472

East Asian (EAS) AF: 0.296 AC: 1530 AN: 5168

South Asian (SAS) AF: 0.959 AC: 4626 AN: 4822

European-Finnish (FIN) AF: 0.997 AC: 10586 AN: 10618

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.964 AC: 65617 AN: 68036

Other (OTH) AF: 0.884 AC: 1861 AN: 2106

Alfa AF: 0.950 Hom.: 82607

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
PhyloP100		1.2
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1229984; hg19: chr4-100239319; COSMIC: COSV59295640;