9-136431867-C-T
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_019892.6(INPP5E):c.1506G>A(p.Pro502=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,609,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 29)
Exomes 𝑓: 0.0012 ( 2 hom. )
Consequence
INPP5E
NM_019892.6 synonymous
NM_019892.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0160
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 -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
Variant 9-136431867-C-T is Benign according to our data. Variant chr9-136431867-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 365880.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr9-136431867-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.016 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00104 (156/149496) while in subpopulation NFE AF= 0.00193 (130/67370). AF 95% confidence interval is 0.00166. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INPP5E | NM_019892.6 | c.1506G>A | p.Pro502= | synonymous_variant | 7/10 | ENST00000371712.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.1506G>A | p.Pro502= | synonymous_variant | 7/10 | 1 | NM_019892.6 | P1 | |
INPP5E | ENST00000676019.1 | c.1404G>A | p.Pro468= | synonymous_variant | 7/10 |
Frequencies
GnomAD3 genomes AF: 0.00104 AC: 156AN: 149378Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.000861 AC: 212AN: 246178Hom.: 0 AF XY: 0.00101 AC XY: 135AN XY: 134188
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GnomAD4 exome AF: 0.00117 AC: 1709AN: 1460074Hom.: 2 Cov.: 36 AF XY: 0.00119 AC XY: 866AN XY: 726382
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GnomAD4 genome AF: 0.00104 AC: 156AN: 149496Hom.: 0 Cov.: 29 AF XY: 0.00108 AC XY: 79AN XY: 72890
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | INPP5E: BP4, BP7 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Joubert syndrome 1 Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Familial aplasia of the vermis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
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Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at