rs28933977

Positions:

chr6-131884939-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006208.3(ENPP1):c.2320C>T(p.Arg774Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,628 control chromosomes in the GnomAD database, including 1,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.028 ( 108 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1120 hom. )

Consequence

ENPP1
NM_006208.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:1

Conservation

PhyloP100: 1.82

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:

ENPP1 (HGNC:):

ENPP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044817626).

BP6

Variant 6-131884939-C-T is Benign according to our data. Variant chr6-131884939-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13586.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, not_provided=1, Benign=3}. Variant chr6-131884939-C-T is described in Lovd as [Pathogenic]. Variant chr6-131884939-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0282 (4298/152234) while in subpopulation NFE AF= 0.0366 (2491/68020). AF 95% confidence interval is 0.0354. There are 108 homozygotes in gnomad4. There are 2250 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 108 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3 linkuse as main transcript	c.2320C>T	p.Arg774Cys	missense_variant	23/25	ENST00000647893.1	NP_006199.2	P22413

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ENPP1	ENST00000647893.1 linkuse as main transcript	c.2320C>T	p.Arg774Cys	missense_variant	23/25		NM_006208.3	ENSP00000498074.1	P22413
ENPP1	ENST00000513998.5 linkuse as main transcript	n.*1157C>T		non_coding_transcript_exon_variant	23/25	5		ENSP00000422424.1	E9PE72
ENPP1	ENST00000684674.1 linkuse as main transcript	n.751C>T		non_coding_transcript_exon_variant	4/6
ENPP1	ENST00000513998.5 linkuse as main transcript	n.*1157C>T		3_prime_UTR_variant	23/25	5		ENSP00000422424.1	E9PE72

Frequencies

GnomAD3 genomes

AF:

0.0283

AC:

4300

AN:

152116

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00558

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0357

Gnomad FIN

AF:

0.0925

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0366

Gnomad OTH

AF:

0.0311

GnomAD3 exomes

AF:

0.0331

AC:

8311

AN:

251400

Hom.:

236

AF XY:

0.0345

AC XY:

4687

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0398

Gnomad FIN exome

AF:

0.0973

Gnomad NFE exome

AF:

0.0367

Gnomad OTH exome

AF:

0.0336

GnomAD4 exome

AF:

0.0344

AC:

50339

AN:

1461394

Hom.:

1120

Cov.:

AF XY:

0.0349

AC XY:

25405

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00460

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0134

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0402

Gnomad4 FIN exome

AF:

0.0971

Gnomad4 NFE exome

AF:

0.0347

Gnomad4 OTH exome

AF:

0.0319

GnomAD4 genome

AF:

0.0282

AC:

4298

AN:

152234

Hom.:

108

Cov.:

AF XY:

0.0302

AC XY:

2250

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00556

Gnomad4 AMR

AF:

0.0147

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0355

Gnomad4 FIN

AF:

0.0925

Gnomad4 NFE

AF:

0.0366

Gnomad4 OTH

AF:

0.0308

Alfa

AF:

0.0312

Hom.:

113

Bravo

AF:

0.0212

TwinsUK

AF:

0.0313

AC:

116

ALSPAC

AF:

0.0335

AC:

129

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0365

AC:

314

ExAC

AF:

0.0332

AC:

4028

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arterial calcification, generalized, of infancy, 1

Benign:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	literature only	OMIM	Feb 12, 2010	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 344/13006=2.64% -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2018	This variant is associated with the following publications: (PMID: 22995991, 20981092, 21228398, 12881724, 27884173, 27467858) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Type 2 diabetes mellitus

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

ENPP1 gene 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. However, the role of rs28933977 in type 2 diabetes remains uncertain. -

Hypophosphatemic rickets, autosomal recessive, 2

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T

Eigen

Benign

0.027

Eigen_PC

Benign

0.018

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.80

.;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.2

L;L

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.26

Sift

Uncertain

0.0080

D;.

Sift4G

Uncertain

0.025

D;.

Polyphen

0.97

D;D

Vest4

0.14

MPC

0.75

ClinPred

0.038

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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