4-99127235-C-A

Position:

• chr4-99127235-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000670.5(ADH4):​c.953G>T​(p.Arg318Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH4	NM_000670.5	c.953G>T	p.Arg318Leu	missense_variant	7/9	ENST00000265512.12	NP_000661.2
LOC100507053	NR_037884.1	n.429-6320C>A		intron_variant, non_coding_transcript_variant
ADH4	NM_001306171.2	c.1010G>T	p.Arg337Leu	missense_variant	8/10		NP_001293100.1
ADH4	NM_001306172.2	c.1010G>T	p.Arg337Leu	missense_variant	8/10		NP_001293101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH4	ENST00000265512.12	c.953G>T	p.Arg318Leu	missense_variant	7/9	1	NM_000670.5	ENSP00000265512	P1
	ENST00000500358.6	n.429-6320C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.953G>T (p.R318L) alteration is located in exon 7 (coding exon 7) of the ADH4 gene. This alteration results from a G to T substitution at nucleotide position 953, causing the arginine (R) at amino acid position 318 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	.;T;T;.
Eigen	Benign	0.16
Eigen_PC	Benign	-0.0046
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	.;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-6.5	D;.;D;D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.96	D;.;P;D
Vest4		0.63
MutPred		0.81		.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;
MVP		0.52
MPC		0.25
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.87
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100048386;