4-99144358-T-G

Variant names:

• chr4-99144358-T-G
• rs1800759
• ENST00000500358.6:n.680-10187T>G

Variant summary

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

The ENST00000500358.6(ENSG00000246090):​n.680-10187T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 832,468 control chromosomes in the GnomAD database, including 155,044 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 0.50 (21619 hom., cov: 31)
  • Exomes 𝑓: 0.62 (133425 hom.)
• Consequence: ENSG00000246090 ENST00000500358.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 65 publications found

Genes affected

ENSG00000246090 (HGNC:):

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC100507053	NR_037884.1	n.680-10187T>G		intron_variant	Intron 2 of 9
ADH4	NM_000670.5	c.-136A>C		upstream_gene_variant		ENST00000265512.12	NP_000661.2
ADH4	NM_001306171.2	c.-227A>C		upstream_gene_variant			NP_001293100.1
ADH4	NM_001306172.2	c.-219A>C		upstream_gene_variant			NP_001293101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.-136A>C		upstream_gene_variant		1	NM_000670.5	ENSP00000265512.7

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75940 AN: 151898 Hom.: 21616 Cov.: 31

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.799

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.653

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.515

GnomAD4 exome AF: 0.615 AC: 418577 AN: 680452 Hom.: 133425 AF XY: 0.625 AC XY: 225031 AN XY: 359780

African (AFR) AF: 0.227 AC: 4056 AN: 17852

American (AMR) AF: 0.421 AC: 14639 AN: 34738

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 11127 AN: 19036

East Asian (EAS) AF: 0.848 AC: 28868 AN: 34056

South Asian (SAS) AF: 0.799 AC: 48986 AN: 61302

European-Finnish (FIN) AF: 0.575 AC: 22590 AN: 39306

Middle Eastern (MID) AF: 0.618 AC: 2469 AN: 3996

European-Non Finnish (NFE) AF: 0.609 AC: 265502 AN: 436174

Other (OTH) AF: 0.598 AC: 20340 AN: 33992

GnomAD4 genome AF: 0.500 AC: 75962 AN: 152016 Hom.: 21619 Cov.: 31 AF XY: 0.507 AC XY: 37686 AN XY: 74296

African (AFR) AF: 0.233 AC: 9654 AN: 41478

American (AMR) AF: 0.454 AC: 6934 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2009 AN: 3468

East Asian (EAS) AF: 0.857 AC: 4435 AN: 5174

South Asian (SAS) AF: 0.799 AC: 3852 AN: 4820

European-Finnish (FIN) AF: 0.578 AC: 6100 AN: 10554

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.606 AC: 41142 AN: 67942

Other (OTH) AF: 0.519 AC: 1096 AN: 2110

Alfa AF: 0.551 Hom.: 42732

Bravo AF: 0.471

Asia WGS AF: 0.744 AC: 2585 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		1.7
PromoterAI		-0.26	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800759; hg19: chr4-100065509; COSMIC: COSV55501258;