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rs13297509

chr9-136431830-G-Achr9-136431830-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_019892.6(INPP5E):c.1543C>T(p.Arg515Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,524,546 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. R515Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000082 ( 0 hom., cov: 21)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

INPP5E
NM_019892.6 missense

Scores

3
7
9

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.18
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.909
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 9-136431830-G-A is Pathogenic according to our data. Variant chr9-136431830-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-136431830-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INPP5ENM_019892.6 linkuse as main transcriptc.1543C>T p.Arg515Trp missense_variant 7/10 ENST00000371712.4
INPP5ENM_001318502.2 linkuse as main transcriptc.1540C>T p.Arg514Trp missense_variant 7/10
INPP5EXM_017014926.2 linkuse as main transcriptc.1543C>T p.Arg515Trp missense_variant 7/10
INPP5EXM_047423603.1 linkuse as main transcriptc.1540C>T p.Arg514Trp missense_variant 7/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INPP5EENST00000371712.4 linkuse as main transcriptc.1543C>T p.Arg515Trp missense_variant 7/101 NM_019892.6 P1Q9NRR6-1
INPP5EENST00000676019.1 linkuse as main transcriptc.1441C>T p.Arg481Trp missense_variant 7/10 Q9NRR6-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00000818
AC:
1
AN:
122306
Hom.:
0
Cov.:
21
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000170
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000377
AC:
9
AN:
238850
Hom.:
0
AF XY:
0.0000534
AC XY:
7
AN XY:
131146
show subpopulations
Gnomad AFR exome
AF:
0.000342
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000591
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000280
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000128
AC:
18
AN:
1402240
Hom.:
0
Cov.:
36
AF XY:
0.0000172
AC XY:
12
AN XY:
697262
show subpopulations
Gnomad4 AFR exome
AF:
0.0000630
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000305
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000139
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00000818
AC:
1
AN:
122306
Hom.:
0
Cov.:
21
AF XY:
0.00
AC XY:
0
AN XY:
58406
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000170
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000203
Hom.:
0
Bravo
AF:
0.0000302
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000166
AC:
2
EpiCase
AF:
0.0000549
EpiControl
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Joubert syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2009- -
Familial aplasia of the vermis Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeMay 24, 2023This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 515 of the INPP5E protein (p.Arg515Trp). This variant is present in population databases (rs13297509, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of Joubert syndrome or retinitis pigmentosa (PMID: 19668216, 27081510, 28559085; Invitae). ClinVar contains an entry for this variant (Variation ID: 397). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on INPP5E protein function. Experimental studies have shown that this missense change affects INPP5E function (PMID: 19668216). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.15
Cadd
Benign
19
Dann
Benign
0.97
DEOGEN2
Pathogenic
0.83
D
Eigen
Benign
-0.90
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.47
N
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
0.98
N
PrimateAI
Benign
0.28
T
PROVEAN
Uncertain
-3.5
D
REVEL
Uncertain
0.37
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.0060
D
Polyphen
1.0
D
Vest4
0.73
MutPred
0.50
Loss of disorder (P = 0.0349);
MVP
0.84
MPC
0.79
ClinPred
0.35
T
GERP RS
-4.3
Varity_R
0.28
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs13297509; hg19: chr9-139326282; COSMIC: COSV65495925; COSMIC: COSV65495925; API