4-99419115-C-G

Variant names:

• chr4-99419115-C-G
• rs150551313
• NM_000673.7:c.832G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000673.7(ADH7):​c.832G>C​(p.Ala278Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A278T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADH7 NM_000673.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000673.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH7	NM_000673.7	MANE Select	c.832G>C	p.Ala278Pro	missense	Exon 7 of 9	NP_000664.3	A0A0C4DG85
	ADH7	NM_001166504.2		c.892G>C	p.Ala298Pro	missense	Exon 7 of 9	NP_001159976.1	P40394-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH7	ENST00000437033.7	TSL:1 MANE Select	c.832G>C	p.Ala278Pro	missense	Exon 7 of 9	ENSP00000414254.2	A0A0C4DG85
	ADH7	ENST00000209665.8	TSL:1	c.868G>C	p.Ala290Pro	missense	Exon 7 of 9	ENSP00000209665.4	P40394-1
	ADH7	ENST00000476959.5	TSL:2	c.892G>C	p.Ala298Pro	missense	Exon 7 of 9	ENSP00000420269.1	P40394-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		4.3
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.76		Gain of catalytic residue at A290 (P = 0.0966)
MVP		0.51
MPC		0.023
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.96
gMVP		0.91
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150551313; hg19: chr4-100340272;