chr4-99136512-C-G

Variant names:

• chr4-99136512-C-G
• rs367666785
• NM_000670.5:c.536G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000670.5(ADH4):​c.536G>C​(p.Gly179Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G179V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH4	NM_000670.5	c.536G>C	p.Gly179Ala	missense_variant	Exon 5 of 9	ENST00000265512.12	NP_000661.2
ADH4	NM_001306171.2	c.593G>C	p.Gly198Ala	missense_variant	Exon 6 of 10		NP_001293100.1
ADH4	NM_001306172.2	c.593G>C	p.Gly198Ala	missense_variant	Exon 6 of 10		NP_001293101.1
LOC100507053	NR_037884.1	n.679+2707C>G		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.536G>C	p.Gly179Ala	missense_variant	Exon 5 of 9	1	NM_000670.5	ENSP00000265512.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	.;T;T;.;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.;.
PhyloP100		2.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.4	D;.;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.025	D;.;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;.;.
Polyphen		1.0	D;.;P;D;.;.
Vest4		0.65
MutPred		0.77		.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;.;.;
MVP		0.45
MPC		0.29
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.83
gMVP		0.77
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs367666785; hg19: chr4-100057663;