rs2066702

Positions:

• chr4-99307860-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BA1

The NM_000668.6(ADH1B):​c.1108C>T​(p.Arg370Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,550 control chromosomes in the GnomAD database, including 1,461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.054 (756 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (705 hom.)
• Consequence: ADH1B NM_000668.6 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 3.37

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 -11 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ADH1B_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020994842).
• BP6: Variant 4-99307860-G-A is Benign according to our data. Variant chr4-99307860-G-A is described in ClinVar as [protective]. Clinvar id is 18183.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_benign, oryginal submission is: [protective].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH1B	NM_000668.6	c.1108C>T	p.Arg370Cys	missense_variant	9/9	ENST00000305046.13	NP_000659.2
ADH1B	NM_001286650.2	c.988C>T	p.Arg330Cys	missense_variant	10/10		NP_001273579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH1B	ENST00000305046.13	c.1108C>T	p.Arg370Cys	missense_variant	9/9	1	NM_000668.6	ENSP00000306606	P1
ADH1B	ENST00000625860.2	c.988C>T	p.Arg330Cys	missense_variant	9/9	1		ENSP00000486614
ADH1B	ENST00000506651.5	c.988C>T	p.Arg330Cys	missense_variant	10/10	2		ENSP00000425998
ADH1B	ENST00000515694.4	n.3203C>T		non_coding_transcript_exon_variant	9/9	2

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8277 AN: 151978 Hom.: 757 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0393

GnomAD3 exomes AF: 0.0150 AC: 3780 AN: 251340 Hom.: 306 AF XY: 0.0116 AC XY: 1579 AN XY: 135870

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.00823

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00638 AC: 9326 AN: 1461454 Hom.: 705 Cov.: 30 AF XY: 0.00566 AC XY: 4116 AN XY: 727070

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.00953

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.0545 AC: 8286 AN: 152096 Hom.: 756 Cov.: 32 AF XY: 0.0529 AC XY: 3936 AN XY: 74364

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0171

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.0389

Alfa AF: 0.0136 Hom.: 254

Bravo AF: 0.0624

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.187 AC: 824

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0182 AC: 2205

Asia WGS AF: 0.00866 AC: 31 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00302

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Alcohol dependence Benign:1

protective, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;T;.
Eigen	Uncertain	0.45
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D;.;D
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.1e-12	P;P
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.9	D;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D;.;.;.
Sift4G	Uncertain	0.017	D;D;D;.
Vest4		0.32
MPC		0.83
ClinPred		0.10	T
GERP RS		3.1
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2066702; hg19: chr4-100229017; COSMIC: COSV105895189;