6-131674262-C-A

Variant names:

• chr6-131674262-C-A
• rs202198426
• NM_005021.5:c.743C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005021.5(ENPP3):​c.743C>A​(p.Ala248Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENPP3 NM_005021.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.207

Genes affected

ENPP3 (HGNC:3358): (ectonucleotide pyrophosphatase/phosphodiesterase 3) The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09564316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP3	NM_005021.5	c.743C>A	p.Ala248Asp	missense_variant	Exon 8 of 25	ENST00000357639.8	NP_005012.2
ENPP3	XM_017010932.2	c.512C>A	p.Ala171Asp	missense_variant	Exon 6 of 23		XP_016866421.1
ENPP3	NR_133007.2	n.826C>A		non_coding_transcript_exon_variant	Exon 8 of 24
ENPP3	XM_011535897.2	c.-149C>A		upstream_gene_variant			XP_011534199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP3	ENST00000357639.8	c.743C>A	p.Ala248Asp	missense_variant	Exon 8 of 25	1	NM_005021.5	ENSP00000350265.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.743C>A (p.A248D) alteration is located in exon 8 (coding exon 8) of the ENPP3 gene. This alteration results from a C to A substitution at nucleotide position 743, causing the alanine (A) at amino acid position 248 to be replaced by an aspartic acid (D). 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	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.080	T;T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.69	.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.50	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.026	B;B;.
Vest4		0.20
MutPred		0.45		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.41
MPC		0.095
ClinPred		0.067	T
GERP RS		-1.0
Varity_R		0.23
gMVP		0.77

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: rs202198426; hg19: chr6-131995402;