6-131860504-C-A

Position:

chr6-131860504-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_006208.3(ENPP1):c.913C>A(p.Pro305Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,589,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ENPP1
NM_006208.3 missense, splice_region

Scores

Splicing: ADA: 0.9159

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 7.31

Variant links:

Genes affected

ENPP1 (HGNC:3356): (ectonucleotide pyrophosphatase/phosphodiesterase 1) This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with 'idiopathic' infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. [provided by RefSeq, Jul 2008]

ENPP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

PP5

Variant 6-131860504-C-A is Pathogenic according to our data. Variant chr6-131860504-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 29842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-131860504-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3 linkuse as main transcript	c.913C>A	p.Pro305Thr	missense_variant, splice_region_variant	8/25	ENST00000647893.1	NP_006199.2	P22413

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1 linkuse as main transcript	c.913C>A	p.Pro305Thr	missense_variant, splice_region_variant	8/25		NM_006208.3	ENSP00000498074.1		P22413

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249804

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000104

AC:

149

AN:

1436950

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

716488

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.000202

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arterial calcification, generalized, of infancy, 1

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The ENPP1 c.913C>A (p.Pro305Thr) missense variant has been described in at least four studies in which it was found in a total of 19 individuals with generalized arterial calcification of infancy, including in seven in a homozygous state and in 12 in a compound heterozygous state, including three sibling pairs, with most patients reported to have died in infancy (Ruf et al. 2005; Ciana et al. 2006; Rutsch et al. 2008; Stella et al. 2016). The p.Pro305Thr variant was absent from 85 controls. The variant is reported at a frequency of 0.00023 in the African American population of the Exome Sequencing Project but this is based on only one allele in a region of adequate sequencing coverage so the variant is presumed to be rare. The Pro305 residue is highly conserved and located in the catalytic domain of the protein. Functional studies in which the variant was transfected into HEK293 cells show that the p.Pro305Thr variant results in a complete loss of activity and extracellular PPi generation compared to wild type. The variant localized to the plasma membrane similarly to wild type but is predicted to have a structural impact effect on protein stability (Stella et al. 2016). Based on the collective evidence, the p.Pro305Thr variant is classified as pathogenic for generalized arterial calcification of infancy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2022	Published functional studies demonstrate a damaging effect on enzyme activity (Stella et al., 2016); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15605415, 16315058, 33465815, 27467858, 29244957, 28973083, 32172442, 33005041, 20016754) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 305 of the ENPP1 protein (p.Pro305Thr). This variant is present in population databases (rs374270497, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive arterial calcification (PMID: 15605415, 27467858, 28973083, 29244957, 33005041). ClinVar contains an entry for this variant (Variation ID: 29842). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ENPP1 function (PMID: 27467858). For these reasons, this variant has been classified as Pathogenic. -

ENPP1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2024

The ENPP1 c.913C>A variant is predicted to result in the amino acid substitution p.Pro305Thr. This variant in the compound heterozygous or homozygous condition has been well documented to be pathogenic for generalized arterial calcification of infancy (Meng et al. 2017. PubMed ID: 28973083; Rutsch et al. 2008. PubMed ID: 20016754; Ferreira et al. 2020. PubMed ID: 33005041). Functional analysis indicated that the p.Pro305Thr variant abolished ENPP enzyme activity (Stella et al. 2016. PubMed ID: 27467858). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Pathogenic

4.0

H;H

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.9

D;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.97

MVP

0.91

MPC

0.84

ClinPred

1.0

GERP RS

5.3

Varity_R

0.93

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.80

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over