6-131685448-C-T

Variant summary

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

The NM_005021.5(ENPP3):c.1205C>T(p.Pro402Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000226 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: ENPP3 NM_005021.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP3	NM_005021.5	c.1205C>T	p.Pro402Leu	missense_variant	13/25	ENST00000357639.8
ENPP3	XM_017010932.2	c.974C>T	p.Pro325Leu	missense_variant	11/23
ENPP3	XM_011535897.2	c.443C>T	p.Pro148Leu	missense_variant	6/18
ENPP3	NR_133007.2	n.1288C>T		non_coding_transcript_exon_variant	13/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP3	ENST00000357639.8	c.1205C>T	p.Pro402Leu	missense_variant	13/25	1	NM_005021.5	P1
ENPP3	ENST00000414305.5	c.1205C>T	p.Pro402Leu	missense_variant	14/26	1		P1
ENPP3	ENST00000358229.6	c.1205C>T	p.Pro402Leu	missense_variant	13/24	1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251274 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135824

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000230 AC: 336 AN: 1461702 Hom.: 0 Cov.: 30 AF XY: 0.000204 AC XY: 148 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000265

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74412

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.00

EpiControl AF: 0.000119

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

Jan 03, 2022

The c.1205C>T (p.P402L) alteration is located in exon 13 (coding exon 13) of the ENPP3 gene. This alteration results from a C to T substitution at nucleotide position 1205, causing the proline (P) at amino acid position 402 to be replaced by a leucine (L). 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	0.56
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.4	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.1	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.83
MVP		0.90
MPC		0.38
ClinPred		0.71	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147313737; hg19: chr6-132006588;