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rs1044498

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. 13/19 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

17

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]

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 UniProt
ENPP1NM_006208.3 linkuse as main transcriptc.517A>C p.Lys173Gln missense_variant 4/25 ENST00000647893.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ENPP1ENST00000647893.1 linkuse as main transcriptc.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.:
32
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.:
33
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.:
32
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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterclinical testingGenome-Nilou LabJul 30, 2021- -
Arterial calcification, generalized, of infancy, 1 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 30, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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, flagged submissionclinical testingLaboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New DelhiMar 07, 2022- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 24, 2015- -
Type 2 diabetes mellitus Benign:1
Benign, criteria provided, single submitterresearchClinical 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 submitterclinical testingGenome-Nilou LabJul 30, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
ENPP1-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 23, 2020This 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 providedliterature onlyOMIMAug 15, 2016- -
Diabetes mellitus type 2, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMDec 01, 2006- -
Obesity Other:1
risk factor, no assertion criteria providedliterature onlyOMIMDec 01, 2006- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.73
T
BayesDel_noAF
Benign
-0.68
Cadd
Benign
15
Dann
Benign
0.93
DEOGEN2
Benign
0.40
T;T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.051
N
MetaRNN
Benign
9.3e-7
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;L
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.24
T
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
T
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.

Other links and lift over

dbSNP: rs1044498; hg19: chr6-132172368; COSMIC: COSV62932133; API