rs267606784

Positions:

chr6-131858735-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006208.3(ENPP1):c.783C>G(p.Tyr261Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000412 in 1,455,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ENPP1
NM_006208.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 5.43

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-131858735-C-G is Pathogenic according to our data. Variant chr6-131858735-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13597.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-131858735-C-G is described in Lovd as [Pathogenic]. Variant chr6-131858735-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3 linkuse as main transcript	c.783C>G	p.Tyr261Ter	stop_gained	7/25	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ENPP1	ENST00000647893.1 linkuse as main transcript	c.783C>G	p.Tyr261Ter	stop_gained	7/25		NM_006208.3	ENSP00000498074	P1
ENPP1	ENST00000513998.5 linkuse as main transcript	c.783C>G	p.Tyr261Ter	stop_gained, NMD_transcript_variant	7/25	5		ENSP00000422424
ENPP1	ENST00000650147.1 linkuse as main transcript	c.*68C>G		3_prime_UTR_variant, NMD_transcript_variant	4/7			ENSP00000497519
ENPP1	ENST00000650437.1 linkuse as main transcript	c.*68C>G		3_prime_UTR_variant, NMD_transcript_variant	3/14			ENSP00000497981

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250396

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135338

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1455106

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Arterial calcification, generalized, of infancy, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 13, 2012

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 13597). This premature translational stop signal has been observed in individual(s) with ENPP1-related conditions (PMID: 19206175, 29141319; Invitae). This variant is present in population databases (rs267606784, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Tyr261*) in the ENPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENPP1 are known to be pathogenic (PMID: 12881724, 15605415, 16369898, 20016754, 20137773, 22539483). -

ENPP1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The ENPP1 c.783C>G variant is predicted to result in premature protein termination (p.Tyr261*). This variant has been reported to be causative for autosomal recessive generalized arterial calcification of infancy (see for example - Rutsch et al. 2003. PubMed ID: 12881724; Xiong et al. 2015. PubMed ID: 25525159). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in ENPP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

Vest4

0.97

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

Position offset: 12

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