rs374270497

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_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:6O:1

Conservation

PhyloP100: 7.31

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

arterial calcification, generalized, of infancy, 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
hypopigmentation-punctate palmoplantar keratoderma syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
hypophosphatemic rickets, autosomal recessive, 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
arterial calcification of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive hypophosphatemic rickets
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive inherited pseudoxanthoma elasticum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENPP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

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 VariationId is 29842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3 link	c.913C>A	p.Pro305Thr	missense_variant, splice_region_variant	Exon 8 of 25	ENST00000647893.1	NP_006199.2	P22413

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1 link	c.913C>A	p.Pro305Thr	missense_variant, splice_region_variant	Exon 8 of 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

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

249804

AF XY:

0.0000222

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 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

African (AFR)

AF:

0.0000305

AC:

AN:

32810

American (AMR)

AF:

0.00

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25918

East Asian (EAS)

AF:

0.00

AC:

AN:

39404

South Asian (SAS)

AF:

0.00

AC:

AN:

85570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4938

European-Non Finnish (NFE)

AF:

0.000125

AC:

136

AN:

1090952

Other (OTH)

AF:

0.000202

AC:

AN:

59438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000101

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:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arterial calcification, generalized, of infancy, 1

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 06, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Type 2 diabetes mellitus;C2750078:Hypophosphatemic rickets, autosomal recessive, 2;C3809781:Hypopigmentation-punctate palmoplantar keratoderma syndrome;C4054476:Inherited obesity;C4551985:Arterial calcification, generalized, of infancy, 1

Pathogenic:1

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ENPP1-related disorder

Pathogenic:1

Jun 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

7.3

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

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over