rs2213035

Positions:

• chr4-99143082-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000670.5(ADH4):​c.19-302C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 693,344 control chromosomes in the GnomAD database, including 21,072 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 0.21 (4045 hom., cov: 31)
  • Exomes 𝑓: 0.23 (17027 hom.)
• Consequence: ADH4 NM_000670.5 intron
• Scores: Splicing: ADA: 0.00004877
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.607

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH4	NM_000670.5	c.19-302C>T		intron_variant		ENST00000265512.12	NP_000661.2
LOC100507053	NR_037884.1	n.679+9277G>A		intron_variant, non_coding_transcript_variant
ADH4	NM_001306171.2	c.75+84C>T		intron_variant			NP_001293100.1
ADH4	NM_001306172.2	c.75+84C>T		intron_variant			NP_001293101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.19-302C>T		intron_variant		1	NM_000670.5	ENSP00000265512	P1
	ENST00000500358.6	n.679+9277G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31954 AN: 151604 Hom.: 4048 Cov.: 31

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.240

GnomAD3 exomes AF: 0.196 AC: 24929 AN: 127264 Hom.: 3101 AF XY: 0.198 AC XY: 13826 AN XY: 69754

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.00135

Gnomad SAS exome AF: 0.130

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.233 AC: 126109 AN: 541630 Hom.: 17027 Cov.: 0 AF XY: 0.231 AC XY: 67670 AN XY: 293462

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.00157

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.211 AC: 31955 AN: 151714 Hom.: 4045 Cov.: 31 AF XY: 0.203 AC XY: 15055 AN XY: 74098

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.00175

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.238

Alfa AF: 0.255 Hom.: 1016

Bravo AF: 0.203

Asia WGS AF: 0.0680 AC: 237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.6
DANN	Benign	0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs2213035; hg19: chr4-100064233;