chr6-131808036-A-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_006208.3(ENPP1):āc.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
NM_006208.3 start_lost
Scores
6
2
8
Clinical Significance
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]
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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 |
---|---|---|---|---|---|---|---|
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
GnomAD3 genomes
Cov.:
19
GnomAD4 exome AF: 0.00000305 AC: 2AN: 654774Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0AN XY: 303064
GnomAD4 exome
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2
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654774
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5
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Gnomad4 AFR exome
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GnomAD4 genome Cov.: 19
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 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
P;P
Vest4
MutPred
Gain of MoRF binding (P = 0.1179);Gain of MoRF binding (P = 0.1179);
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.