rs1044498

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006208.3(ENPP1):c.517A>C(p.Lys173Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,613,790 control chromosomes in the GnomAD database, including 41,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 14194 hom., cov: 32)

Exomes 𝑓: 0.16 ( 26814 hom. )

Consequence

ENPP1
NM_006208.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:9O:3

Conservation

PhyloP100: 1.45

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.3244637E-7).

BP6

Variant 6-131851228-A-C is Benign according to our data. Variant chr6-131851228-A-C is described in ClinVar as [Benign]. Clinvar id is 13589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-131851228-A-C is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3 linkuse as main transcript	c.517A>C	p.Lys173Gln	missense_variant	4/25	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1 linkuse as main transcript	c.517A>C	p.Lys173Gln	missense_variant	4/25		NM_006208.3	ENSP00000498074	P1

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49878

AN:

152022

Hom.:

14135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.775

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.232

Gnomad EAS

AF:

0.0944

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.295

GnomAD3 exomes

AF:

0.195

AC:

48946

AN:

251206

Hom.:

8046

AF XY:

0.183

AC XY:

24803

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.786

Gnomad AMR exome

AF:

0.188

Gnomad ASJ exome

AF:

0.219

Gnomad EAS exome

AF:

0.0977

Gnomad SAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.128

Gnomad NFE exome

AF:

0.146

Gnomad OTH exome

AF:

0.181

GnomAD4 exome

AF:

0.162

AC:

236113

AN:

1461650

Hom.:

26814

Cov.:

AF XY:

0.159

AC XY:

115934

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.798

Gnomad4 AMR exome

AF:

0.193

Gnomad4 ASJ exome

AF:

0.222

Gnomad4 EAS exome

AF:

0.0933

Gnomad4 SAS exome

AF:

0.171

Gnomad4 FIN exome

AF:

0.128

Gnomad4 NFE exome

AF:

0.141

Gnomad4 OTH exome

AF:

0.199

GnomAD4 genome

AF:

0.329

AC:

49999

AN:

152140

Hom.:

14194

Cov.:

AF XY:

0.322

AC XY:

23968

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.776

Gnomad4 AMR

AF:

0.245

Gnomad4 ASJ

AF:

0.232

Gnomad4 EAS

AF:

0.0942

Gnomad4 SAS

AF:

0.177

Gnomad4 FIN

AF:

0.122

Gnomad4 NFE

AF:

0.142

Gnomad4 OTH

AF:

0.296

Alfa

AF:

0.174

Hom.:

6482

Bravo

AF:

0.356

TwinsUK

AF:

0.143

AC:

530

ALSPAC

AF:

0.141

AC:

543

ESP6500AA

AF:

0.751

AC:

3310

ESP6500EA

AF:

0.145

AC:

1245

ExAC

AF:

0.206

AC:

25043

Asia WGS

AF:

0.163

AC:

570

AN:

3478

EpiCase

AF:

0.151

EpiControl

AF:

0.150

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:9Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypophosphatemic rickets, autosomal recessive, 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Arterial calcification, generalized, of infancy, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Hypophosphatemic rickets

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi

Mar 07, 2022

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 24, 2015

- -

Type 2 diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

rs1044498 of ENPP1 is associated with type 2 diabetes mellitus and increased insulin resistance. It is also associated with calcification of coronary artery disease, increasing the chances of macrovascular complications in diabetes. -

Hypopigmentation-punctate palmoplantar keratoderma syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

ENPP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2020

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

Insulin resistance, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 15, 2016

- -

Diabetes mellitus type 2, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2006

- -

Obesity

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.40

T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.37

.;T

MetaRNN

Benign

9.3e-7

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.055

Sift

Benign

0.32

T;.

Sift4G

Benign

0.38

T;.

Polyphen

0.072

B;B

Vest4

0.031

MPC

0.22

ClinPred

0.016

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.086

gMVP

0.59

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

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