4-99142704-G-A

Variant summary

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

The NM_000670.5(ADH4):c.95C>T(p.Pro32Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,600,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P32R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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 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=0.12595925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH4	NM_000670.5	c.95C>T	p.Pro32Leu	missense_variant	2/9	ENST00000265512.12
LOC100507053	NR_037884.1	n.679+8899G>A		intron_variant, non_coding_transcript_variant
ADH4	NM_001306171.2	c.152C>T	p.Pro51Leu	missense_variant	3/10
ADH4	NM_001306172.2	c.152C>T	p.Pro51Leu	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH4	ENST00000265512.12	c.95C>T	p.Pro32Leu	missense_variant	2/9	1	NM_000670.5	P1
	ENST00000500358.6	n.679+8899G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 51 AN: 241658 Hom.: 0 AF XY: 0.000221 AC XY: 29 AN XY: 131134

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.0000312

Gnomad ASJ exome AF: 0.00292

Gnomad EAS exome AF: 0.0000574

Gnomad SAS exome AF: 0.000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000110 AC: 160 AN: 1448458 Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 87 AN XY: 720474

Gnomad4 AFR exome AF: 0.0000611

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00339

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.000321

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.000403

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74298

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000173 AC: 21

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

Dec 03, 2021

The c.95C>T (p.P32L) alteration is located in exon 2 (coding exon 2) of the ADH4 gene. This alteration results from a C to T substitution at nucleotide position 95, causing the proline (P) at amino acid position 32 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	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-9.2	D;.;D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	D;.;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;.;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.49
MVP		0.55
MPC		0.080
ClinPred		0.39	T
GERP RS		2.5
Varity_R		0.79
gMVP		0.60

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: rs145793949; hg19: chr4-100063855;