rs1126670

Positions:

• chr4-99131582-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_000670.5(ADH4):​c.765G>T​(p.Pro255=) 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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH4	NM_000670.5	c.765G>T	p.Pro255=	synonymous_variant	6/9	ENST00000265512.12	NP_000661.2
LOC100507053	NR_037884.1	n.429-1973C>A		intron_variant, non_coding_transcript_variant
ADH4	NM_001306171.2	c.822G>T	p.Pro274=	synonymous_variant	7/10		NP_001293100.1
ADH4	NM_001306172.2	c.822G>T	p.Pro274=	synonymous_variant	7/10		NP_001293101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.765G>T	p.Pro255=	synonymous_variant	6/9	1	NM_000670.5	ENSP00000265512	P1
	ENST00000500358.6	n.429-1973C>A		intron_variant, non_coding_transcript_variant		1

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

GnomAD3 exomes AF: 0.757 AC: 190332 AN: 251332 Hom.: 73329 AF XY: 0.755 AC XY: 102600 AN XY: 135842

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 SAS exome AF: 0.853

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

Gnomad4 AFR exome AF: 0.829

Gnomad4 AMR exome AF: 0.791

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: 0.695

Gnomad4 OTH exome AF: 0.732

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

Gnomad4 AFR AF: 0.824

Gnomad4 AMR AF: 0.751

Gnomad4 ASJ AF: 0.674

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.864

Gnomad4 FIN AF: 0.710

Gnomad4 NFE AF: 0.687

Gnomad4 OTH AF: 0.732

Alfa AF: 0.706 Hom.: 68187

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.9
DANN	Benign	0.51

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: rs1126670; hg19: chr4-100052733;