4-99420682-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000673.7(ADH7):c.676A>G(p.Lys226Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 1,613,840 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (174 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (181 hom.)
• Consequence: ADH7 NM_000673.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.58

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026580095).
• BP6: Variant 4-99420682-T-C is Benign according to our data. Variant chr4-99420682-T-C is described in ClinVar as [Benign]. Clinvar id is 776001.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADH7	NM_000673.7	c.676A>G	p.Lys226Glu	missense_variant	6/9	ENST00000437033.7
ADH7	NM_001166504.2	c.736A>G	p.Lys246Glu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADH7	ENST00000437033.7	c.676A>G	p.Lys226Glu	missense_variant	6/9	1	NM_000673.7	P1
ADH7	ENST00000209665.8	c.712A>G	p.Lys238Glu	missense_variant	6/9	1
ADH7	ENST00000476959.5	c.736A>G	p.Lys246Glu	missense_variant	6/9	2
ADH7	ENST00000482593.5	c.505A>G	p.Lys169Glu	missense_variant	7/10	3

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3937 AN: 152050 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.00721 AC: 1811 AN: 251158 Hom.: 81 AF XY: 0.00537 AC XY: 729 AN XY: 135726

Gnomad AFR exome AF: 0.0913

Gnomad AMR exome AF: 0.00545

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000933

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00318 AC: 4644 AN: 1461672 Hom.: 181 Cov.: 32 AF XY: 0.00278 AC XY: 2025 AN XY: 727126

Gnomad4 AFR exome AF: 0.0953

Gnomad4 AMR exome AF: 0.00651

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000654

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.0258 AC: 3933 AN: 152168 Hom.: 174 Cov.: 32 AF XY: 0.0258 AC XY: 1922 AN XY: 74402

Gnomad4 AFR AF: 0.0890

Gnomad4 AMR AF: 0.00883

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.00486 Hom.: 51

Bravo AF: 0.0299

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0858 AC: 378

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00868 AC: 1054

Asia WGS AF: 0.00635 AC: 23 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.66
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.097	T;T;.;.
Eigen	Benign	0.033
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.98	L;.;.;.
MutationTaster	Benign	0.22	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.079
Sift	Benign	0.40	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.95	P;.;.;.
Vest4		0.15
MVP		0.55
MPC		0.057
ClinPred		0.022	T
GERP RS		2.6
Varity_R		0.18
gMVP		0.37

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: rs59534319; hg19: chr4-100341839;