6-131808037-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_006208.3(ENPP1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 766,792 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ENPP1
NM_006208.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.458

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 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP1	NM_006208.3 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/25	ENST00000647893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ENPP1	ENST00000647893.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/25		NM_006208.3	P1
ENPP1	ENST00000486853.1 linkuse as main transcript	n.22T>C		non_coding_transcript_exon_variant	1/4	2
ENPP1	ENST00000513998.5 linkuse as main transcript	c.2T>C	p.Met1?	start_lost, NMD_transcript_variant	1/25	5

Frequencies

GnomAD3 genomes

AF:

0.0000687

AC:

AN:

72740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000389

AC:

AN:

694028

Hom.:

Cov.:

AF XY:

0.0000435

AC XY:

AN XY:

322080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000748

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00173

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000158

Gnomad4 OTH exome

AF:

0.0000441

GnomAD4 genome

AF:

0.0000550

AC:

AN:

72764

Hom.:

Cov.:

AF XY:

0.0000896

AC XY:

AN XY:

33480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00200

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2023

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with ENPP1-related conditions. This sequence change affects the initiator methionine of the ENPP1 mRNA. The next in-frame methionine is located at codon 53. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.080

Cadd

Benign

Dann

Benign

0.85

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.54

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.29

MutationTaster

Benign

1.0

PROVEAN

Benign

-0.36

N;.

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.93

P;P

Vest4

0.51

MutPred

0.98

Gain of phosphorylation at M1 (P = 0.005);Gain of phosphorylation at M1 (P = 0.005);

MVP

0.86

ClinPred

0.41

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.79

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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