rs1126671

Positions:

• chr4-99127263-T-C
• chr4-99127263-T-G

Variant summary

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

The ENST00000265512.12(ADH4):​c.925A>G​(p.Ile309Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.722 in 1,610,424 control chromosomes in the GnomAD database, including 423,736 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.75 (43118 hom., cov: 31)
  • Exomes 𝑓: 0.72 (380618 hom.)
• Consequence: ADH4 ENST00000265512.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88

Genes affected

ADH4 (HGNC:252): (alcohol dehydrogenase 4 (class II), pi polypeptide) This gene encodes class II alcohol dehydrogenase 4 pi subunit, which 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. Class II alcohol dehydrogenase is a homodimer composed of 2 pi subunits. It exhibits a high activity for oxidation of long-chain aliphatic alcohols and aromatic alcohols and is less sensitive to pyrazole. This gene is localized to chromosome 4 in the cluster of alcohol dehydrogenase genes. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3259082E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH4	NM_000670.5	c.925A>G	p.Ile309Val	missense_variant	7/9	ENST00000265512.12	NP_000661.2
LOC100507053	NR_037884.1	n.429-6292T>C		intron_variant, non_coding_transcript_variant
ADH4	NM_001306171.2	c.982A>G	p.Ile328Val	missense_variant	8/10		NP_001293100.1
ADH4	NM_001306172.2	c.982A>G	p.Ile328Val	missense_variant	8/10		NP_001293101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.925A>G	p.Ile309Val	missense_variant	7/9	1	NM_000670.5	ENSP00000265512	P1
	ENST00000500358.6	n.429-6292T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113627 AN: 151784 Hom.: 43071 Cov.: 31

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.864

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.728

GnomAD3 exomes AF: 0.757 AC: 188734 AN: 249482 Hom.: 72686 AF XY: 0.754 AC XY: 101762 AN XY: 134874

Gnomad AFR exome AF: 0.827

Gnomad AMR exome AF: 0.796

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.853

Gnomad FIN exome AF: 0.707

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.719 AC: 1048776 AN: 1458522 Hom.: 380618 Cov.: 40 AF XY: 0.721 AC XY: 523529 AN XY: 725678

Gnomad4 AFR exome AF: 0.829

Gnomad4 AMR exome AF: 0.790

Gnomad4 ASJ exome AF: 0.674

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.852

Gnomad4 FIN exome AF: 0.700

Gnomad4 NFE exome AF: 0.694

Gnomad4 OTH exome AF: 0.731

GnomAD4 genome AF: 0.749 AC: 113735 AN: 151902 Hom.: 43118 Cov.: 31 AF XY: 0.757 AC XY: 56172 AN XY: 74220

Gnomad4 AFR AF: 0.825

Gnomad4 AMR AF: 0.749

Gnomad4 ASJ AF: 0.674

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.864

Gnomad4 FIN AF: 0.713

Gnomad4 NFE AF: 0.687

Gnomad4 OTH AF: 0.731

Alfa AF: 0.701 Hom.: 89973

Bravo AF: 0.753

TwinsUK AF: 0.686 AC: 2543

ALSPAC AF: 0.695 AC: 2680

ESP6500AA AF: 0.823 AC: 3626

ESP6500EA AF: 0.684 AC: 5880

ExAC AF: 0.756 AC: 91767

Asia WGS AF: 0.908 AC: 3158 AN: 3478

EpiCase AF: 0.683

EpiControl AF: 0.683

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0070
DANN	Benign	0.28
DEOGEN2	Benign	0.0069	.;T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.19	.;T;T;T
MetaRNN	Benign	0.0000013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.30	.;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N;.;N;N
REVEL	Benign	0.017
Sift	Benign	0.89	T;.;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.018
MPC		0.034
ClinPred		0.0031	T
GERP RS		-7.3
Varity_R		0.033
gMVP		0.43

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: rs1126671; hg19: chr4-100048414; COSMIC: COSV55501980; COSMIC: COSV55501980;