chr4-99313896-A-G

Variant names:

• chr4-99313896-A-G
• rs1789882
• NM_000668.6:c.753T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000668.6(ADH1B):​c.753T>C​(p.Ile251Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 1,612,934 control chromosomes in the GnomAD database, including 542,042 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (50000 hom., cov: 31)
  • Exomes 𝑓: 0.82 (492042 hom.)
• Consequence: ADH1B NM_000668.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00800
• Publications: 32 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-0.008 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000668.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1B	NM_000668.6	MANE Select	c.753T>C	p.Ile251Ile	synonymous	Exon 6 of 9	NP_000659.2
	ADH1B	NM_001286650.2		c.633T>C	p.Ile211Ile	synonymous	Exon 7 of 10	NP_001273579.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1B	ENST00000305046.13	TSL:1 MANE Select	c.753T>C	p.Ile251Ile	synonymous	Exon 6 of 9	ENSP00000306606.8
	ADH1B	ENST00000625860.2	TSL:1	c.633T>C	p.Ile211Ile	synonymous	Exon 6 of 9	ENSP00000486614.1
	ADH1B	ENST00000506651.5	TSL:2	c.633T>C	p.Ile211Ile	synonymous	Exon 7 of 10	ENSP00000425998.2

Frequencies

GnomAD3 genomes AF: 0.810 AC: 123131 AN: 151960 Hom.: 49954 Cov.: 31

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.926

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.845

Gnomad EAS AF: 0.914

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.826

GnomAD2 exomes AF: 0.815 AC: 204755 AN: 251142 AF XY: 0.814

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.793

Gnomad ASJ exome AF: 0.844

Gnomad EAS exome AF: 0.918

Gnomad FIN exome AF: 0.800

Gnomad NFE exome AF: 0.831

Gnomad OTH exome AF: 0.824

GnomAD4 exome AF: 0.820 AC: 1198119 AN: 1460856 Hom.: 492042 Cov.: 95 AF XY: 0.820 AC XY: 595568 AN XY: 726744

African (AFR) AF: 0.765 AC: 25594 AN: 33468

American (AMR) AF: 0.798 AC: 35698 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 22080 AN: 26118

East Asian (EAS) AF: 0.921 AC: 36553 AN: 39700

South Asian (SAS) AF: 0.756 AC: 65157 AN: 86240

European-Finnish (FIN) AF: 0.809 AC: 43203 AN: 53418

Middle Eastern (MID) AF: 0.783 AC: 4514 AN: 5764

European-Non Finnish (NFE) AF: 0.825 AC: 916102 AN: 1111080

Other (OTH) AF: 0.815 AC: 49218 AN: 60354

GnomAD4 genome AF: 0.810 AC: 123230 AN: 152078 Hom.: 50000 Cov.: 31 AF XY: 0.808 AC XY: 60038 AN XY: 74336

African (AFR) AF: 0.769 AC: 31891 AN: 41474

American (AMR) AF: 0.815 AC: 12433 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 2929 AN: 3468

East Asian (EAS) AF: 0.914 AC: 4725 AN: 5170

South Asian (SAS) AF: 0.764 AC: 3684 AN: 4822

European-Finnish (FIN) AF: 0.799 AC: 8454 AN: 10576

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56301 AN: 67998

Other (OTH) AF: 0.822 AC: 1734 AN: 2110

Alfa AF: 0.826 Hom.: 16728

Bravo AF: 0.812

Asia WGS AF: 0.767 AC: 2663 AN: 3476

EpiCase AF: 0.834

EpiControl AF: 0.840

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.7
DANN	Benign	0.77
PhyloP100		-0.0080
Mutation Taster		=100/0	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: rs1789882; hg19: chr4-100235053; COSMIC: COSV108104067; COSMIC: COSV108104067;