4-99420699-A-T

Position:

• chr4-99420699-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000673.7(ADH7):​c.659T>A​(p.Ile220Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADH7 NM_000673.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.35

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH7	NM_000673.7	c.659T>A	p.Ile220Asn	missense_variant	6/9	ENST00000437033.7	NP_000664.3
ADH7	NM_001166504.2	c.719T>A	p.Ile240Asn	missense_variant	6/9		NP_001159976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH7	ENST00000437033.7	c.659T>A	p.Ile220Asn	missense_variant	6/9	1	NM_000673.7	ENSP00000414254	P1
ADH7	ENST00000209665.8	c.695T>A	p.Ile232Asn	missense_variant	6/9	1		ENSP00000209665
ADH7	ENST00000476959.5	c.719T>A	p.Ile240Asn	missense_variant	6/9	2		ENSP00000420269
ADH7	ENST00000482593.5	c.488T>A	p.Ile163Asn	missense_variant	7/10	3		ENSP00000420613

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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 07, 2021

The c.695T>A (p.I232N) alteration is located in exon 6 (coding exon 6) of the ADH7 gene. This alteration results from a T to A substitution at nucleotide position 695, causing the isoleucine (I) at amino acid position 232 to be replaced by an asparagine (N). 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	0.97
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	4.5	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.82		Loss of stability (P = 0.0049);.;.;.;
MVP		0.39
MPC		0.19
ClinPred		1.0	D
GERP RS		2.6
Varity_R		0.96
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100341856;