rs78828148
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_019892.6(INPP5E):c.1388-13C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,612,606 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.014 ( 42 hom., cov: 30)
Exomes 𝑓: 0.0014 ( 38 hom. )
Consequence
INPP5E
NM_019892.6 splice_polypyrimidine_tract, intron
NM_019892.6 splice_polypyrimidine_tract, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.24
Genes affected
INPP5E (HGNC:21474): (inositol polyphosphate-5-phosphatase E) The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. Studies of the mouse counterpart suggest that this protein may hydrolyze phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,5-bisphosphate on the cytoplasmic Golgi membrane and thereby regulate Golgi-vesicular trafficking. Mutations in this gene cause Joubert syndrome; a clinically and genetically heterogenous group of disorders characterized by midbrain-hindbrain malformation and various associated ciliopathies that include retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
?
Variant 9-136431998-G-A is Benign according to our data. Variant chr9-136431998-G-A is described in ClinVar as [Benign]. Clinvar id is 261195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136431998-G-A is described in Lovd as [Likely_benign]. Variant chr9-136431998-G-A is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0137 (2081/152158) while in subpopulation AFR AF= 0.0482 (1998/41492). AF 95% confidence interval is 0.0464. There are 42 homozygotes in gnomad4. There are 961 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 42 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INPP5E | NM_019892.6 | c.1388-13C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000371712.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.1388-13C>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_019892.6 | P1 | |||
INPP5E | ENST00000676019.1 | c.1286-13C>T | splice_polypyrimidine_tract_variant, intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0137 AC: 2078AN: 152040Hom.: 42 Cov.: 30
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GnomAD3 exomes AF: 0.00365 AC: 906AN: 247900Hom.: 19 AF XY: 0.00264 AC XY: 356AN XY: 134840
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GnomAD4 exome AF: 0.00135 AC: 1976AN: 1460448Hom.: 38 Cov.: 36 AF XY: 0.00113 AC XY: 818AN XY: 726536
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GnomAD4 genome ? AF: 0.0137 AC: 2081AN: 152158Hom.: 42 Cov.: 30 AF XY: 0.0129 AC XY: 961AN XY: 74394
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Joubert syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Familial aplasia of the vermis Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at