rs28933977

chr6-131884939-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R774H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (108 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1120 hom.)
• Consequence: ENPP1 NM_006208.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 1.82

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 -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: {not_provided=1, Likely_benign=3, Benign=3, Uncertain_significance=1}. 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 109 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP1	NM_006208.3	c.2320C>T	p.Arg774Cys	missense_variant	23/25	ENST00000647893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP1	ENST00000647893.1	c.2320C>T	p.Arg774Cys	missense_variant	23/25		NM_006208.3	P1
ENPP1	ENST00000684674.1	n.751C>T		non_coding_transcript_exon_variant	4/6
ENPP1	ENST00000513998.5	c.*1157C>T		3_prime_UTR_variant, NMD_transcript_variant	23/25	5

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4300 AN: 152116 Hom.: 109 Cov.: 32

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

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.: 32 AF XY: 0.0349 AC XY: 25405 AN XY: 727026

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.: 32 AF XY: 0.0302 AC XY: 2250 AN XY: 74414

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: 30

ESP6500EA AF: 0.0365 AC: 314

ExAC AF: 0.0332 AC: 4028

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arterial calcification, generalized, of infancy, 1 Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, no assertion criteria provided	literature only	OMIM	Feb 12, 2010	- -
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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2014	- -
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% -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
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) -

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	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	0.027
Eigen_PC	Benign	0.018
FATHMM_MKL	Benign	0.67	D
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.21	T
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	T
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

Other links and lift over

dbSNP: rs28933977; hg19: chr6-132206079;