4-99127263-T-C

Variant names:

• chr4-99127263-T-C
• rs1126671
• NM_000670.5:c.925A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000670.5(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. 15/21 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. I309F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.75 (43118 hom., cov: 31)
  • Exomes 𝑓: 0.72 (380618 hom.)
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 75 publications found

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]

ENSG00000246090 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000670.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH4	NM_000670.5	MANE Select	c.925A>G	p.Ile309Val	missense	Exon 7 of 9	NP_000661.2	P08319-1
	ADH4	NM_001306171.2		c.982A>G	p.Ile328Val	missense	Exon 8 of 10	NP_001293100.1	P08319-2
	ADH4	NM_001306172.2		c.982A>G	p.Ile328Val	missense	Exon 8 of 10	NP_001293101.1	P08319-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH4	ENST00000265512.12	TSL:1 MANE Select	c.925A>G	p.Ile309Val	missense	Exon 7 of 9	ENSP00000265512.7	P08319-1
	ENSG00000246090	ENST00000500358.6	TSL:1	n.429-6292T>C		intron	N/A
	ADH4	ENST00000505590.5	TSL:5	c.982A>G	p.Ile328Val	missense	Exon 8 of 10	ENSP00000425416.1	P08319-2

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

GnomAD2 exomes AF: 0.757 AC: 188734 AN: 249482 AF XY: 0.754

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 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

African (AFR) AF: 0.829 AC: 27615 AN: 33300

American (AMR) AF: 0.790 AC: 35168 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 17558 AN: 26048

East Asian (EAS) AF: 0.998 AC: 39517 AN: 39584

South Asian (SAS) AF: 0.852 AC: 73195 AN: 85916

European-Finnish (FIN) AF: 0.700 AC: 37351 AN: 53368

Middle Eastern (MID) AF: 0.742 AC: 4264 AN: 5748

European-Non Finnish (NFE) AF: 0.694 AC: 770099 AN: 1109848

Other (OTH) AF: 0.731 AC: 44009 AN: 60208

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

African (AFR) AF: 0.825 AC: 34175 AN: 41440

American (AMR) AF: 0.749 AC: 11420 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2339 AN: 3468

East Asian (EAS) AF: 0.998 AC: 5169 AN: 5180

South Asian (SAS) AF: 0.864 AC: 4159 AN: 4814

European-Finnish (FIN) AF: 0.713 AC: 7479 AN: 10492

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46647 AN: 67940

Other (OTH) AF: 0.731 AC: 1542 AN: 2110

Alfa AF: 0.711 Hom.: 141435

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 v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.30	N
PhyloP100		-1.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.017
Sift	Benign	0.89	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.034
ClinPred		0.0031	T
GERP RS		-7.3
Varity_R		0.033
gMVP		0.43
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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