4-99127263-T-G

Position:

• chr4-99127263-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000670.5(ADH4):​c.925A>C​(p.Ile309Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I309V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07115093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH4	NM_000670.5	c.925A>C	p.Ile309Leu	missense_variant	7/9	ENST00000265512.12	NP_000661.2
ADH4	NM_001306171.2	c.982A>C	p.Ile328Leu	missense_variant	8/10		NP_001293100.1
ADH4	NM_001306172.2	c.982A>C	p.Ile328Leu	missense_variant	8/10		NP_001293101.1
LOC100507053	NR_037884.1	n.429-6292T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.925A>C	p.Ile309Leu	missense_variant	7/9	1	NM_000670.5	ENSP00000265512.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1459518 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 726142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.052
DANN	Benign	0.47
DEOGEN2	Benign	0.0087	.;T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.17	.;T;T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.071	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.20	.;.;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.46	N;.;N;N
REVEL	Benign	0.014
Sift	Benign	0.56	T;.;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.11
MutPred		0.38		.;Loss of catalytic residue at P311 (P = 0.0712);Loss of catalytic residue at P311 (P = 0.0712);.;
MVP		0.18
MPC		0.038
ClinPred		0.033	T
GERP RS		-7.3
Varity_R		0.064
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs1126671; hg19: chr4-100048414;