4-99427978-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000673.7(ADH7):c.359G>A(p.Arg120His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,864 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (7 hom.)
• Consequence: ADH7 NM_000673.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.81

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012828529).
• BP6: Variant 4-99427978-C-T is Benign according to our data. Variant chr4-99427978-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3033494.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH7	NM_000673.7	c.359G>A	p.Arg120His	missense_variant	5/9	ENST00000437033.7
ADH7	NM_001166504.2	c.419G>A	p.Arg140His	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH7	ENST00000437033.7	c.359G>A	p.Arg120His	missense_variant	5/9	1	NM_000673.7	P1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 235 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00119 AC: 299 AN: 251070 Hom.: 2 AF XY: 0.00116 AC XY: 158 AN XY: 135676

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00235 AC: 3432 AN: 1461646 Hom.: 7 Cov.: 32 AF XY: 0.00228 AC XY: 1656 AN XY: 727122

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00198

Gnomad4 NFE exome AF: 0.00287

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00155 AC XY: 115 AN XY: 74426

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00287

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00208 Hom.: 2

Bravo AF: 0.00122

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00122 AC: 148

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ADH7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.2
Dann	Benign	0.96
DEOGEN2	Benign	0.086	T;T;.;.;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.83	T;T;T;T;D
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.64	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.078	T;T;T;T;.
Polyphen		0.0020	B;.;.;.;.
Vest4		0.052
MVP		0.21
MPC		0.021
ClinPred		0.019	T
GERP RS		0.45
Varity_R		0.19
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs284797; hg19: chr4-100349135;