rs121918025

Variant names:

• chr6-131861704-G-T
• rs121918025
• NM_006208.3:c.1025G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_006208.3(ENPP1):​c.1025G>T​(p.Gly342Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,376,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G342G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ENPP1 NM_006208.3 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.71
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• arterial calcification, generalized, of infancy, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hypopigmentation-punctate palmoplantar keratoderma syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• hypophosphatemic rickets, autosomal recessive, 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hypophosphatemic rickets

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive inherited pseudoxanthoma elasticum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 6-131861704-G-T is Pathogenic according to our data. Variant chr6-131861704-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.1025G>T	p.Gly342Val	missense_variant, splice_region_variant	Exon 9 of 25	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.1025G>T	p.Gly342Val	missense_variant, splice_region_variant	Exon 9 of 25		NM_006208.3	ENSP00000498074.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1376774 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 690142

African (AFR) AF: 0.00 AC: 0 AN: 31800

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39230

South Asian (SAS) AF: 0.00 AC: 0 AN: 84538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 9.67e-7 AC: 1 AN: 1034422

Other (OTH) AF: 0.00 AC: 0 AN: 57540

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jul 15, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with valine at codon 342 of the ENPP1 protein (p.Gly342Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with autosomal recessive generalized arterial calcification of infancy (PMID: 15940697). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13591). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Coronary sclerosis, medial, of infancy Pathogenic:1

Jul 17, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant is also predicted to affect the canonical splice donor site of intron 9 of 25 by multiple splice prediction tools, and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with generalized arterial calcification of infancy (PMID: 15605415, 15940697). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1025G>T, p.Gly342Val variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.70
DEOGEN2	Uncertain	0.57	D;D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		1.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.33
Sift	Benign	0.24	T;.
Sift4G	Benign	0.17	T;.
Polyphen		0.031	B;B
Vest4		0.25
MutPred		0.61		Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);
MVP		0.83
MPC		0.29
ClinPred		0.88	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.82
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.44		Position offset: 0

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

Other links and lift over

dbSNP: rs121918025; hg19: chr6-132182844;