4-99419054-G-A

Position:

• chr4-99419054-G-A

Variant summary

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

The NM_000673.7(ADH7):​c.893C>T​(p.Ala298Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADH7 NM_000673.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.30

Genes affected

ADH7 (HGNC:256): (alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide) This gene encodes class IV alcohol dehydrogenase 7 mu or sigma subunit, which is a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. The enzyme encoded by this gene is inefficient in ethanol oxidation, but is the most active as a retinol dehydrogenase; thus it may participate in the synthesis of retinoic acid, a hormone important for cellular differentiation. The expression of this gene is much more abundant in stomach than liver, thus differing from the other known gene family members. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

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=0.22810015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH7	NM_000673.7	c.893C>T	p.Ala298Val	missense_variant	7/9	ENST00000437033.7	NP_000664.3
ADH7	NM_001166504.2	c.953C>T	p.Ala318Val	missense_variant	7/9		NP_001159976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH7	ENST00000437033.7	c.893C>T	p.Ala298Val	missense_variant	7/9	1	NM_000673.7	ENSP00000414254	P1
ADH7	ENST00000209665.8	c.929C>T	p.Ala310Val	missense_variant	7/9	1		ENSP00000209665
ADH7	ENST00000476959.5	c.953C>T	p.Ala318Val	missense_variant	7/9	2		ENSP00000420269
ADH7	ENST00000482593.5	c.722C>T	p.Ala241Val	missense_variant	8/10	3		ENSP00000420613

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251054 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461578 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.929C>T (p.A310V) alteration is located in exon 7 (coding exon 7) of the ADH7 gene. This alteration results from a C to T substitution at nucleotide position 929, causing the alanine (A) at amino acid position 310 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ADH7-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2024

The ADH7 c.953C>T variant is predicted to result in the amino acid substitution p.Ala318Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.21	T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	0.89	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.093
Sift	Benign	0.10	T;T;D;T
Sift4G	Uncertain	0.053	T;T;T;T
Polyphen		0.18	B;.;.;.
Vest4		0.29
MutPred		0.62		Loss of ubiquitination at K311 (P = 0.0777);.;.;.;
MVP		0.44
MPC		0.022
ClinPred		0.78	D
GERP RS		4.5
Varity_R		0.24
gMVP		0.47

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: rs1433147867; hg19: chr4-100340211;