6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_006208.3(ENPP1):c.313+41_313+46dupGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.011 ( 12 hom., cov: 0)
Exomes 𝑓: 0.0057 ( 2 hom. )
Consequence
ENPP1
NM_006208.3 intron
NM_006208.3 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.525
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_benign. Variant got -5 ACMG points.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1562/137248) while in subpopulation NFE AF= 0.0167 (1065/63794). AF 95% confidence interval is 0.0159. There are 12 homozygotes in gnomad4. There are 717 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 12 AR gene
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ENPP1 | ENST00000647893.1 | c.313+8_313+9insGTGTGT | intron_variant | NM_006208.3 | ENSP00000498074.1 | |||||
ENPP1 | ENST00000486853.1 | n.333+8_333+9insGTGTGT | intron_variant | 2 | ||||||
ENPP1 | ENST00000513998.5 | n.313+8_313+9insGTGTGT | intron_variant | 5 | ENSP00000422424.1 | |||||
ENPP1 | ENST00000650507.1 | n.*149+8_*149+9insGTGTGT | intron_variant | ENSP00000497375.1 |
Frequencies
GnomAD3 genomes AF: 0.0114 AC: 1560AN: 137160Hom.: 12 Cov.: 0
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GnomAD4 exome AF: 0.00569 AC: 5938AN: 1042824Hom.: 2 Cov.: 14 AF XY: 0.00593 AC XY: 3132AN XY: 528456
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GnomAD4 genome AF: 0.0114 AC: 1562AN: 137248Hom.: 12 Cov.: 0 AF XY: 0.0107 AC XY: 717AN XY: 66762
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Arterial calcification, generalized, of infancy, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Dec 18, 2024 | - - |
Hypophosphatemic Rickets, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at