rs121918026

Positions:

• chr6-131864886-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_006208.3(ENPP1):​c.1112A>T​(p.Tyr371Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENPP1 NM_006208.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.48

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a disulfide_bond (size 212) in uniprot entity ENPP1_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_006208.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 6-131864886-A-T is Pathogenic according to our data. Variant chr6-131864886-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 13592.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-131864886-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.1112A>T	p.Tyr371Phe	missense_variant	11/25	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.1112A>T	p.Tyr371Phe	missense_variant	11/25		NM_006208.3	ENSP00000498074	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451818 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 722986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arterial calcification, generalized, of infancy, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.67
MutPred		0.62		Loss of phosphorylation at Y371 (P = 0.0193);Loss of phosphorylation at Y371 (P = 0.0193);
MVP		0.86
MPC		0.69
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: 9
DS_AL_spliceai		0.26		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918026; hg19: chr6-132186026;