rs1044498

chr6-131851228-A-Cchr6-131851228-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:9 O:3
• Conservation: PhyloP100: 1.45

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]

ACMG classification

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
ENPP1	NM_006208.3	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	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.: 32

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

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

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

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:1 Benign:9 Other:3

Revision: criteria provided, multiple submitters, no conflicts

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	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, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hypopigmentation-punctate palmoplantar keratoderma syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

ENPP1-related disorder Benign:1

Benign, criteria provided, single submitter

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	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

Other links and lift over

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