rs1044498

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_006208(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 0.328 in 152022 control chromosomes in the gnomAD Genomes database, including 14135 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity (★).

Frequency

Genomes: 𝑓 0.33 ( 14135 hom., cov: 32)

Exomes 𝑓: 0.19 ( 8046 hom. )

Consequence

ENPP1
NM_006208 missense

Scores

Clinical Significance

Conflicting interpretations of pathogenicity criteria provided, conflicting interpretations P:1B:8O:3

Conservation

PhyloP100: 1.45

Links

ENPP1 (HGNC:3356):

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a domain SMB 2 (size 44) in uniprot entity ENPP1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_006208

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 [Conflicting_interpretations_of_pathogenicity]. Clinvar id is 13589. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Likely_pathogenic=1}. Variant chr6-131851228-A-C is described in Lovd as [Likely_pathogenic].

BA1

GnomAd 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	UniProt
ENPP1	NM_006208.3 linkuse as main transcript	c.517A>C	p.Lys173Gln	missense_variant	4/25	ENST00000647893.1

Ensembl

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

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

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: Conflicting interpretations of pathogenicity

Submissions summary: Pathogenic:1Benign:8Other:3

Revision: criteria provided, conflicting interpretations

LINK: link

Submissions by phenotype

Hypophosphatemic rickets, autosomal recessive, 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

Arterial calcification, generalized, of infancy, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

Hypophosphatemic rickets

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

- -

Hypopigmentation-punctate palmoplantar keratoderma syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

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

Find out SpliceAI 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

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over