6-131808036-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_006208.3(ENPP1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: ENPP1 NM_006208.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.91

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 8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP1	NM_006208.3	c.1A>G	p.Met1?	start_lost	1/25	ENST00000647893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP1	ENST00000647893.1	c.1A>G	p.Met1?	start_lost	1/25		NM_006208.3	P1
ENPP1	ENST00000486853.1	n.21A>G		non_coding_transcript_exon_variant	1/4	2
ENPP1	ENST00000513998.5	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	1/25	5

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000305 AC: 2 AN: 654774 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 303064

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: 0.0000761

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000463

GnomAD4 genome Cov.: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2021

The c.1A>G (p.M1?) alteration is located in coding exon 1 of the ENPP1 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 53 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2022

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. 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. 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	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	22
Dann	Benign	0.92
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.083
FATHMM_MKL	Benign	0.51	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.24	N;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.71	P;P
Vest4		0.63
MutPred		0.99		Gain of MoRF binding (P = 0.1179);Gain of MoRF binding (P = 0.1179);
MVP		0.63
ClinPred		0.49	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.80
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-132129176;