4-99141668-A-G

Variant names:

• chr4-99141668-A-G
• rs2032349
• NM_000670.5:c.135T>C

Variant summary

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

The NM_000670.5(ADH4):​c.135T>C​(p.Ser45Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,613,892 control chromosomes in the GnomAD database, including 759,040 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 0.96 (70035 hom., cov: 32)
  • Exomes 𝑓: 0.97 (689005 hom.)
• Consequence: ADH4 NM_000670.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.26
• Publications: 22 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP7: Synonymous conserved (PhyloP=-4.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH4	NM_000670.5	MANE Select	c.135T>C	p.Ser45Ser	synonymous	Exon 3 of 9	NP_000661.2
	ADH4	NM_001306171.2		c.192T>C	p.Ser64Ser	synonymous	Exon 4 of 10	NP_001293100.1
	ADH4	NM_001306172.2		c.192T>C	p.Ser64Ser	synonymous	Exon 4 of 10	NP_001293101.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH4	ENST00000265512.12	TSL:1 MANE Select	c.135T>C	p.Ser45Ser	synonymous	Exon 3 of 9	ENSP00000265512.7
	ENSG00000246090	ENST00000500358.6	TSL:1	n.679+7863A>G		intron	N/A
	ADH4	ENST00000505590.5	TSL:5	c.192T>C	p.Ser64Ser	synonymous	Exon 4 of 10	ENSP00000425416.1

Frequencies

GnomAD3 genomes AF: 0.959 AC: 145895 AN: 152118 Hom.: 69985 Cov.: 32

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.957

Gnomad ASJ AF: 0.973

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.979

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.968

GnomAD2 exomes AF: 0.965 AC: 242326 AN: 251158 AF XY: 0.969

Gnomad AFR exome AF: 0.931

Gnomad AMR exome AF: 0.933

Gnomad ASJ exome AF: 0.980

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.942

Gnomad NFE exome AF: 0.972

Gnomad OTH exome AF: 0.965

GnomAD4 exome AF: 0.971 AC: 1419026 AN: 1461656 Hom.: 689005 Cov.: 44 AF XY: 0.972 AC XY: 706435 AN XY: 727136

African (AFR) AF: 0.931 AC: 31156 AN: 33460

American (AMR) AF: 0.934 AC: 41731 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 25560 AN: 26124

East Asian (EAS) AF: 1.00 AC: 39682 AN: 39688

South Asian (SAS) AF: 0.982 AC: 84685 AN: 86246

European-Finnish (FIN) AF: 0.941 AC: 50289 AN: 53418

Middle Eastern (MID) AF: 0.986 AC: 5686 AN: 5766

European-Non Finnish (NFE) AF: 0.973 AC: 1081526 AN: 1111882

Other (OTH) AF: 0.972 AC: 58711 AN: 60380

GnomAD4 genome AF: 0.959 AC: 146004 AN: 152236 Hom.: 70035 Cov.: 32 AF XY: 0.959 AC XY: 71405 AN XY: 74424

African (AFR) AF: 0.934 AC: 38793 AN: 41532

American (AMR) AF: 0.957 AC: 14629 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.973 AC: 3378 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5174 AN: 5176

South Asian (SAS) AF: 0.979 AC: 4718 AN: 4820

European-Finnish (FIN) AF: 0.945 AC: 10006 AN: 10592

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.971 AC: 66076 AN: 68030

Other (OTH) AF: 0.968 AC: 2049 AN: 2116

Alfa AF: 0.967 Hom.: 198866

Bravo AF: 0.957

Asia WGS AF: 0.977 AC: 3399 AN: 3478

EpiCase AF: 0.977

EpiControl AF: 0.975

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.49
PhyloP100		-4.3
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: rs2032349; hg19: chr4-100062819; COSMIC: COSV108100241;