4-99127235-C-T

Variant names:

• chr4-99127235-C-T
• rs29001219
• NM_000670.5:c.953G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000670.5(ADH4):​c.953G>A​(p.Arg318His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000082 in 1,609,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16973764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH4	NM_000670.5	c.953G>A	p.Arg318His	missense_variant	Exon 7 of 9	ENST00000265512.12	NP_000661.2
ADH4	NM_001306171.2	c.1010G>A	p.Arg337His	missense_variant	Exon 8 of 10		NP_001293100.1
ADH4	NM_001306172.2	c.1010G>A	p.Arg337His	missense_variant	Exon 8 of 10		NP_001293101.1
LOC100507053	NR_037884.1	n.429-6320C>T		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.953G>A	p.Arg318His	missense_variant	Exon 7 of 9	1	NM_000670.5	ENSP00000265512.7

Frequencies

GnomAD3 genomes AF: 0.000323 AC: 49 AN: 151762 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000823

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 247762 AF XY: 0.0000971

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000563 AC: 82 AN: 1457534 Hom.: 0 Cov.: 35 AF XY: 0.0000621 AC XY: 45 AN XY: 724988

African (AFR) AF: 0.000813 AC: 27 AN: 33212

American (AMR) AF: 0.000203 AC: 9 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.000316 AC: 27 AN: 85308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1109776

Other (OTH) AF: 0.0000831 AC: 5 AN: 60204

GnomAD4 genome AF: 0.000329 AC: 50 AN: 151874 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74242

African (AFR) AF: 0.000845 AC: 35 AN: 41438

American (AMR) AF: 0.000393 AC: 6 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67944

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000397

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000549

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	.;T;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	.;.;M;.
PhyloP100		1.6
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.6	D;.;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.50
MVP		0.40
MPC		0.27
ClinPred		0.12	T
GERP RS		2.8
Varity_R		0.67
gMVP		0.72
Mutation Taster		=60/40	polymorphism

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: rs29001219; hg19: chr4-100048386;