rs373044722

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_006208.3(ENPP1):c.1441C>T(p.Arg481Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,382 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R481Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ENPP1
NM_006208.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.00

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 15 ACMG points.

PM1

In a disulfide_bond (size 99) in uniprot entity ENPP1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_006208.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-131872927-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

PP5

Variant 6-131872926-C-T is Pathogenic according to our data. Variant chr6-131872926-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-131872926-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3 link	c.1441C>T	p.Arg481Trp	missense_variant	Exon 15 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.1441C>T	p.Arg481Trp	missense_variant	Exon 15 of 25		NM_006208.3	ENSP00000498074.1		P22413

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251146

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135730

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000881

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arterial calcification, generalized, of infancy, 1

Pathogenic:3

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ENPP1 c.1441C>T (p.Arg481Trp) missense variant has been reported in at least two studies and is found in a compound heterozygous state in two unrelated individuals with generalized arterial calcification of infancy (Rutsch et al. 2003; Rutsch et al. 2008). One individual is reported to also have an affected sibling detected from prenatal diagnosis (Rutsch et al. 2008). The p.Arg481Trp variant was absent from 100 controls but is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project but this is based on one allele so the variant is presumed to be rare. Rutsch et al. (2003) performed RT-PCR studies on total RNA from one of the probands that showed that the p.Arg481Trp variant results in skipping of exon 15 which causes a frameshift. Transfection experiments in osteoblastic osteosarcoma cells showed the variant resulted in reduced activity to 30-40% of that associated with wild type ENPP1. The Arg481 residue lies in the catalytic domain of the ENPP1 protein and is conserved in human, mouse and rat ENPP1 and human ENPP3. Based on the evidence, the p.Arg481Trp variant is classified as likely pathogenic for generalized arterial calcification of infancy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 17, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

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 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypophosphatemic rickets, autosomal recessive, 2

Pathogenic:1

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID:12881724). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:12881724). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000547983). A different missense change at the same codon (p.Arg481Gln) has been reported to be associated with ENPP1 related disorder (PMID: 26857895). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1

Jul 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 481 of the ENPP1 protein (p.Arg481Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs373044722, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive ENPP1-related conditions (PMID: 12881724, 29244957, 31826312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 547983). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ENPP1 protein function. Studies have shown that this missense change results in skipping of exon 15, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12881724). For these reasons, this variant has been classified as Pathogenic. -

Hypophosphatemic rickets, autosomal recessive, 2;C4551985:Arterial calcification, generalized, of infancy, 1

Pathogenic:1

Jun 28, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0063

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.97

.;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-5.6

D;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0050

D;.

Polyphen

1.0

D;D

Vest4

0.30

MVP

0.84

MPC

0.75

ClinPred

0.98

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: -3

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