4-99081221-C-T

Variant names:

• chr4-99081221-C-T
• rs896992
• NM_000671.4:c.344+144G>A

Variant summary

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

The NM_000671.4(ADH5):​c.344+144G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 516,232 control chromosomes in the GnomAD database, including 132,969 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 0.69 (35779 hom., cov: 26)
  • Exomes 𝑓: 0.73 (97190 hom.)
• Consequence: ADH5 NM_000671.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.473
• Publications: 4 publications found

Genes affected

ADH5 (HGNC:253): (alcohol dehydrogenase 5 (class III), chi polypeptide) This gene encodes a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. The encoded protein forms a homodimer. It has virtually no activity for ethanol oxidation, but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione. This enzyme is an important component of cellular metabolism for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes lacrymation, rhinitis, pharyngitis, and contact dermatitis. The human genome contains several non-transcribed pseudogenes related to this gene. [provided by RefSeq, Oct 2008]

ADH5 Gene-Disease associations (from GenCC):

• AMED syndrome, digenic

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000671.4. 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
	ADH5	NM_000671.4	MANE Select	c.344+144G>A		intron	N/A	NP_000662.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH5	ENST00000296412.14	TSL:1 MANE Select	c.344+144G>A		intron	N/A	ENSP00000296412.8
	ADH5	ENST00000503130.5	TSL:3	c.305+144G>A		intron	N/A	ENSP00000427049.1
	ADH5	ENST00000626055.2	TSL:5	c.*31+144G>A		intron	N/A	ENSP00000487496.1

Frequencies

GnomAD3 genomes AF: 0.687 AC: 103381 AN: 150410 Hom.: 35762 Cov.: 26

Gnomad AFR AF: 0.641

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.852

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.720

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.671

GnomAD4 exome AF: 0.730 AC: 266910 AN: 365714 Hom.: 97190 AF XY: 0.737 AC XY: 148401 AN XY: 201240

African (AFR) AF: 0.670 AC: 4952 AN: 7388

American (AMR) AF: 0.754 AC: 9215 AN: 12216

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 8206 AN: 12146

East Asian (EAS) AF: 0.998 AC: 18050 AN: 18086

South Asian (SAS) AF: 0.841 AC: 38067 AN: 45290

European-Finnish (FIN) AF: 0.710 AC: 26167 AN: 36862

Middle Eastern (MID) AF: 0.748 AC: 1074 AN: 1436

European-Non Finnish (NFE) AF: 0.692 AC: 147822 AN: 213716

Other (OTH) AF: 0.719 AC: 13357 AN: 18574

GnomAD4 genome AF: 0.687 AC: 103435 AN: 150518 Hom.: 35779 Cov.: 26 AF XY: 0.697 AC XY: 51181 AN XY: 73442

African (AFR) AF: 0.640 AC: 26120 AN: 40806

American (AMR) AF: 0.719 AC: 10859 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2279 AN: 3456

East Asian (EAS) AF: 0.996 AC: 5114 AN: 5132

South Asian (SAS) AF: 0.852 AC: 4013 AN: 4708

European-Finnish (FIN) AF: 0.710 AC: 7331 AN: 10322

Middle Eastern (MID) AF: 0.723 AC: 211 AN: 292

European-Non Finnish (NFE) AF: 0.672 AC: 45509 AN: 67704

Other (OTH) AF: 0.675 AC: 1413 AN: 2094

Alfa AF: 0.680 Hom.: 13523

Bravo AF: 0.681

Asia WGS AF: 0.890 AC: 3092 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		-0.47
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: rs896992; hg19: chr4-100002372;