rs200239821

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_006208.3(ENPP1):c.2336C>A(p.Thr779Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00053 in 1,614,032 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T779P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 9 hom. )

Consequence

ENPP1
NM_006208.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.161

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 Benign. Variant got -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-131884954-A-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.012332797).

BP6

Variant 6-131884955-C-A is Benign according to our data. Variant chr6-131884955-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435061.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.

BS2

High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP1	NM_006208.3 linkuse as main transcript	c.2336C>A	p.Thr779Asn	missense_variant	23/25	ENST00000647893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ENPP1	ENST00000647893.1 linkuse as main transcript	c.2336C>A	p.Thr779Asn	missense_variant	23/25		NM_006208.3	P1
ENPP1	ENST00000684674.1 linkuse as main transcript	n.767C>A		non_coding_transcript_exon_variant	4/6
ENPP1	ENST00000513998.5 linkuse as main transcript	c.*1173C>A		3_prime_UTR_variant, NMD_transcript_variant	23/25	5

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000967

AC:

243

AN:

251406

Hom.:

AF XY:

0.00121

AC XY:

165

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00637

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000548

AC:

801

AN:

1461736

Hom.:

Cov.:

AF XY:

0.000721

AC XY:

524

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00613

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000355

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000352

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000972

AC:

118

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 07, 2016

- -

Arterial calcification, generalized, of infancy, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hypophosphatemic rickets, autosomal recessive, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2023

- -

ENPP1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.028

FATHMM_MKL

Benign

0.13

M_CAP

Benign

0.025

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.7

D;.

REVEL

Benign

0.18

Sift

Benign

0.14

T;.

Sift4G

Benign

0.61

T;.

Polyphen

0.91

P;P

Vest4

0.41

MVP

0.73

MPC

0.47

ClinPred

0.084

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

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