chr6-131808036-A-G

Variant summary

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

The NM_006208.3(ENPP1):ā€‹c.1A>Gā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 19)
Exomes š‘“: 0.0000031 ( 0 hom. )

Consequence

ENPP1
NM_006208.3 start_lost

Scores

6
2
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
ENPP1NM_006208.3 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/25 ENST00000647893.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ENPP1ENST00000647893.1 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/25 NM_006208.3 P1
ENPP1ENST00000486853.1 linkuse as main transcriptn.21A>G non_coding_transcript_exon_variant 1/42
ENPP1ENST00000513998.5 linkuse as main transcriptc.1A>G p.Met1? start_lost, NMD_transcript_variant 1/255

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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
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
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 19, 2021The 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 submitterclinical testingInvitaeSep 23, 2022In 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
LIST_S2
Uncertain
0.90
.;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; API