6-131674262-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.207
Variant links:
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]

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ACMG classification

Classification made for transcript

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
ENPP3NM_005021.5 linkc.743C>A p.Ala248Asp missense_variant Exon 8 of 25 ENST00000357639.8 NP_005012.2 O14638
ENPP3XM_017010932.2 linkc.512C>A p.Ala171Asp missense_variant Exon 6 of 23 XP_016866421.1
ENPP3NR_133007.2 linkn.826C>A non_coding_transcript_exon_variant Exon 8 of 24
ENPP3XM_011535897.2 linkc.-149C>A upstream_gene_variant XP_011534199.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENPP3ENST00000357639.8 linkc.743C>A p.Ala248Asp missense_variant Exon 8 of 25 1 NM_005021.5 ENSP00000350265.3 O14638

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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs202198426; hg19: chr6-131995402; API