rs1044498

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.33 ( 14194 hom., cov: 32)
Exomes 𝑓: 0.16 ( 26814 hom. )

Consequence

ENPP1
NM_006208.3 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:10O: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 was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1
In a disulfide_bond (size 13) in uniprot entity ENPP1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_006208.3
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_classifications_of_pathogenicity]. Clinvar id is 13589.We mark this variant Likely_benign, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Benign=9}. 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 rank MANE Protein UniProt
ENPP1NM_006208.3 linkc.517A>C p.Lys173Gln missense_variant Exon 4 of 25 ENST00000647893.1 NP_006199.2 P22413

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENPP1ENST00000647893.1 linkc.517A>C p.Lys173Gln missense_variant Exon 4 of 25 NM_006208.3 ENSP00000498074.1 P22413

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
GnomAD2 exomes
AF:
0.195
AC:
48946
AN:
251206
AF XY:
0.183
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 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
AC:
26703
AN:
33472
Gnomad4 AMR exome
AF:
0.193
AC:
8616
AN:
44718
Gnomad4 ASJ exome
AF:
0.222
AC:
5790
AN:
26130
Gnomad4 EAS exome
AF:
0.0933
AC:
3702
AN:
39698
Gnomad4 SAS exome
AF:
0.171
AC:
14748
AN:
86258
Gnomad4 FIN exome
AF:
0.128
AC:
6835
AN:
53418
Gnomad4 NFE exome
AF:
0.141
AC:
156371
AN:
1111812
Gnomad4 Remaining exome
AF:
0.199
AC:
12022
AN:
60384
Heterozygous variant carriers
0
10393
20787
31180
41574
51967
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
5926
11852
17778
23704
29630
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
AC:
0.775565
AN:
0.775565
Gnomad4 AMR
AF:
0.245
AC:
0.244575
AN:
0.244575
Gnomad4 ASJ
AF:
0.232
AC:
0.232277
AN:
0.232277
Gnomad4 EAS
AF:
0.0942
AC:
0.094186
AN:
0.094186
Gnomad4 SAS
AF:
0.177
AC:
0.177433
AN:
0.177433
Gnomad4 FIN
AF:
0.122
AC:
0.121716
AN:
0.121716
Gnomad4 NFE
AF:
0.142
AC:
0.142172
AN:
0.142172
Gnomad4 OTH
AF:
0.296
AC:
0.295541
AN:
0.295541
Heterozygous variant carriers
0
1129
2259
3388
4518
5647
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
398
796
1194
1592
1990
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.214
Hom.:
16963
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 classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:10Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypophosphatemic rickets, autosomal recessive, 2 Benign:2
Jul 30, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Jul 30, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Mar 07, 2022
Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Apr 24, 2015
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Type 2 diabetes mellitus Benign:1
-
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:research

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. -

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 Benign:1
Apr 17, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Hypopigmentation-punctate palmoplantar keratoderma syndrome Benign:1
Jul 30, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ENPP1-related disorder Benign:1
Apr 23, 2020
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

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
May 23, 2025
OMIM
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Diabetes mellitus type 2, susceptibility to Other:1
Dec 01, 2006
OMIM
Significance:risk factor
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Obesity Other:1
Dec 01, 2006
OMIM
Significance:risk factor
Review Status:no assertion criteria provided
Collection Method:literature only

- -

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
LIST_S2
Benign
0.37
.;T
MetaRNN
Benign
9.3e-7
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;L
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
Mutation Taster
=99/1
polymorphism (auto)

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