chr4-99131582-C-A

Variant names:

• chr4-99131582-C-A
• rs1126670
• NM_000670.5:c.765G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_000670.5(ADH4):​c.765G>T​(p.Pro255Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 1,613,792 control chromosomes in the GnomAD database, including 425,294 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 0.75 (43205 hom., cov: 31)
  • Exomes 𝑓: 0.72 (382089 hom.)
• Consequence: ADH4 NM_000670.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 35 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP7: Synonymous conserved (PhyloP=0.006 with no splicing effect.
• 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.765G>T	p.Pro255Pro	synonymous	Exon 6 of 9	NP_000661.2	P08319-1
	ADH4	NM_001306171.2		c.822G>T	p.Pro274Pro	synonymous	Exon 7 of 10	NP_001293100.1	P08319-2
	ADH4	NM_001306172.2		c.822G>T	p.Pro274Pro	synonymous	Exon 7 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.765G>T	p.Pro255Pro	synonymous	Exon 6 of 9	ENSP00000265512.7	P08319-1
	ENSG00000246090	ENST00000500358.6	TSL:1	n.429-1973C>A		intron	N/A
	ADH4	ENST00000505590.5	TSL:5	c.822G>T	p.Pro274Pro	synonymous	Exon 7 of 10	ENSP00000425416.1	P08319-2

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113775 AN: 151952 Hom.: 43158 Cov.: 31

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.863

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.729

GnomAD2 exomes AF: 0.757 AC: 190332 AN: 251332 AF XY: 0.755

Gnomad AFR exome AF: 0.827

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.707

Gnomad NFE exome AF: 0.689

Gnomad OTH exome AF: 0.721

GnomAD4 exome AF: 0.720 AC: 1052138 AN: 1461722 Hom.: 382089 Cov.: 56 AF XY: 0.722 AC XY: 525154 AN XY: 727160

African (AFR) AF: 0.829 AC: 27759 AN: 33474

American (AMR) AF: 0.791 AC: 35371 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 17617 AN: 26136

East Asian (EAS) AF: 0.998 AC: 39633 AN: 39700

South Asian (SAS) AF: 0.852 AC: 73496 AN: 86254

European-Finnish (FIN) AF: 0.700 AC: 37376 AN: 53412

Middle Eastern (MID) AF: 0.743 AC: 4277 AN: 5758

European-Non Finnish (NFE) AF: 0.695 AC: 772411 AN: 1111872

Other (OTH) AF: 0.732 AC: 44198 AN: 60392

GnomAD4 genome AF: 0.749 AC: 113883 AN: 152070 Hom.: 43205 Cov.: 31 AF XY: 0.757 AC XY: 56251 AN XY: 74330

African (AFR) AF: 0.824 AC: 34211 AN: 41496

American (AMR) AF: 0.751 AC: 11462 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2339 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5165 AN: 5176

South Asian (SAS) AF: 0.864 AC: 4163 AN: 4820

European-Finnish (FIN) AF: 0.710 AC: 7502 AN: 10560

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46690 AN: 67962

Other (OTH) AF: 0.732 AC: 1545 AN: 2110

Alfa AF: 0.716 Hom.: 111282

Bravo AF: 0.754

Asia WGS AF: 0.908 AC: 3158 AN: 3478

EpiCase AF: 0.683

EpiControl AF: 0.685

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.9
DANN	Benign	0.51
PhyloP100		0.0060
Mutation Taster		=100/0	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: rs1126670; hg19: chr4-100052733; COSMIC: COSV108100237; COSMIC: COSV108100237;