6-46167695-G-C

Position:

• chr6-46167695-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001290072.2(ENPP5):​c.568C>G​(p.Pro190Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENPP5 NM_001290072.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59

Genes affected

ENPP5 (HGNC:13717): (ectonucleotide pyrophosphatase/phosphodiesterase family member 5) This gene encodes a type-I transmembrane glycoprotein. Studies in rat suggest the encoded protein may play a role in neuronal cell communications. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP5	NM_001290072.2	c.568C>G	p.Pro190Ala	missense_variant	3/5	ENST00000371383.7	NP_001277001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP5	ENST00000371383.7	c.568C>G	p.Pro190Ala	missense_variant	3/5	1	NM_001290072.2	ENSP00000360436.1
ENPP5	ENST00000230565.3	c.568C>G	p.Pro190Ala	missense_variant	2/4	1		ENSP00000230565.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Nov 20, 2024

The c.568C>G (p.P190A) alteration is located in exon 2 (coding exon 1) of the ENPP5 gene. This alteration results from a C to G substitution at nucleotide position 568, causing the proline (P) at amino acid position 190 to be replaced by an alanine (A). 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	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.75		Loss of catalytic residue at P190 (P = 0.0591);Loss of catalytic residue at P190 (P = 0.0591);
MVP		0.80
MPC		0.62
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-46135432;