rs10870199
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_019892.6(INPP5E):āc.972A>Gā(p.Pro324=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,609,748 control chromosomes in the GnomAD database, including 16,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.11 ( 1177 hom., cov: 33)
Exomes š: 0.14 ( 15533 hom. )
Consequence
INPP5E
NM_019892.6 synonymous
NM_019892.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.89
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 -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
Variant 9-136434099-T-C is Benign according to our data. Variant chr9-136434099-T-C is described in ClinVar as [Benign]. Clinvar id is 129277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136434099-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.89 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INPP5E | NM_019892.6 | c.972A>G | p.Pro324= | synonymous_variant | 3/10 | ENST00000371712.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.972A>G | p.Pro324= | synonymous_variant | 3/10 | 1 | NM_019892.6 | P1 | |
INPP5E | ENST00000676019.1 | c.972A>G | p.Pro324= | synonymous_variant | 3/10 | ||||
INPP5E | ENST00000675256.1 | c.204A>G | p.Pro68= | synonymous_variant | 2/2 | ||||
INPP5E | ENST00000674513.1 | n.243A>G | non_coding_transcript_exon_variant | 3/3 |
Frequencies
GnomAD3 genomes AF: 0.107 AC: 16345AN: 152126Hom.: 1169 Cov.: 33
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GnomAD3 exomes AF: 0.144 AC: 35124AN: 243562Hom.: 2963 AF XY: 0.142 AC XY: 18822AN XY: 132450
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GnomAD4 exome AF: 0.140 AC: 204771AN: 1457504Hom.: 15533 Cov.: 33 AF XY: 0.141 AC XY: 101996AN XY: 724886
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GnomAD4 genome AF: 0.107 AC: 16359AN: 152244Hom.: 1177 Cov.: 33 AF XY: 0.108 AC XY: 8030AN XY: 74444
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ClinVar
Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2014 | 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. - |
Joubert syndrome 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 19, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
MORM syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 19, 2021 | - - |
Familial aplasia of the vermis Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 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