4-99142702-T-C

Variant summary

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

The NM_000670.5(ADH4):c.97A>G(p.Lys33Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000695 in 1,599,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (1 hom.)
• Consequence: ADH4 NM_000670.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.45

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=0.09768531).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH4	NM_000670.5	c.97A>G	p.Lys33Glu	missense_variant	2/9	ENST00000265512.12
LOC100507053	NR_037884.1	n.679+8897T>C		intron_variant, non_coding_transcript_variant
ADH4	NM_001306171.2	c.154A>G	p.Lys52Glu	missense_variant	3/10
ADH4	NM_001306172.2	c.154A>G	p.Lys52Glu	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH4	ENST00000265512.12	c.97A>G	p.Lys33Glu	missense_variant	2/9	1	NM_000670.5	P1
	ENST00000500358.6	n.679+8897T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000986

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000270 AC: 65 AN: 241112 Hom.: 0 AF XY: 0.000329 AC XY: 43 AN XY: 130822

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.0000941

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.000427

Gnomad OTH exome AF: 0.000516

GnomAD4 exome AF: 0.000707 AC: 1023 AN: 1447504 Hom.: 1 Cov.: 30 AF XY: 0.000694 AC XY: 500 AN XY: 720020

Gnomad4 AFR exome AF: 0.000184

Gnomad4 AMR exome AF: 0.000167

Gnomad4 ASJ exome AF: 0.0000781

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000852

Gnomad4 OTH exome AF: 0.000958

GnomAD4 genome AF: 0.000579 AC: 88 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.000592 AC XY: 44 AN XY: 74360

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.000986

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000547 Hom.: 0

Bravo AF: 0.000518

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000321 AC: 39

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

Jan 18, 2022

The c.97A>G (p.K33E) alteration is located in exon 2 (coding exon 2) of the ADH4 gene. This alteration results from a A to G substitution at nucleotide position 97, causing the lysine (K) at amino acid position 33 to be replaced by a glutamic acid (E). 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	Benign	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.098	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.3	D;.;D;D;D;D
REVEL	Benign	0.099
Sift	Uncertain	0.0040	D;.;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;.;.
Polyphen		0.98	D;.;P;D;.;.
Vest4		0.46
MVP		0.64
MPC		0.080
ClinPred		0.094	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.78
gMVP		0.41

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: rs61754858; hg19: chr4-100063853;