NM_019892.6:c.907G>A
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_019892.6(INPP5E):c.907G>A(p.Val303Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V303L) has been classified as Uncertain significance.
Frequency
Consequence
NM_019892.6 missense
Scores
Clinical Significance
Conservation
Publications
- Joubert syndrome 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
- MORM syndromeInheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, ClinGen, Orphanet
- COACH syndrome 1Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Joubert syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Joubert syndrome with ocular defectInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.907G>A | p.Val303Met | missense_variant | Exon 2 of 10 | 1 | NM_019892.6 | ENSP00000360777.3 | ||
INPP5E | ENST00000676019.1 | c.907G>A | p.Val303Met | missense_variant | Exon 2 of 10 | ENSP00000501984.1 | ||||
INPP5E | ENST00000675256.1 | c.94G>A | p.Val32Met | missense_variant | Exon 1 of 2 | ENSP00000502517.1 | ||||
INPP5E | ENST00000674513.1 | n.178G>A | non_coding_transcript_exon_variant | Exon 2 of 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152068Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000121 AC: 3AN: 246928 AF XY: 0.0000223 show subpopulations
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1459890Hom.: 0 Cov.: 38 AF XY: 0.0000110 AC XY: 8AN XY: 726176 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74424 show subpopulations
ClinVar
Submissions by phenotype
Joubert syndrome Pathogenic:2
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 303 of the INPP5E protein (p.Val303Met). This variant is present in population databases (rs746212325, gnomAD 0.003%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 23386033, 26092869). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217653). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt INPP5E protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1
Published functional studies demonstrate the variant results in reduced protein expression compared to wild type (Cilleros-Rodriguez et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26092869, 23386033, 29987673, 26748598, 33270637, 36063381) -
Joubert syndrome and related disorders Pathogenic:1
Variant summary: INPP5E c.907G>A (p.Val303Met) results in a conservative amino acid change located in the Inositol polyphosphate-related phosphatase domain of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 1.2e-05 in 246928 control chromosomes. c.907G>A has been observed in individual(s) affected with Joubert Syndrome And Related Disorders (Travaglini_2013, Bachmann-Gagescu_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in singificantly reduced ciliary localization (Cilleros-Rodriguez_2022). The following publications have been ascertained in the context of this evaluation (PMID: 26092869, 33270637, 36063381, 29987673, 23386033). ClinVar contains an entry for this variant (Variation ID: 217653). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at