NM_019892.6:c.1684A>G
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_019892.6(INPP5E):c.1684A>G(p.Ser562Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S562S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
INPP5E
NM_019892.6 missense
NM_019892.6 missense
Scores
7
5
6
Clinical Significance
Conservation
PhyloP100: 7.09
Publications
0 publications found
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]
INPP5E Gene-Disease associations (from GenCC):
- Joubert syndrome 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
- MORM syndromeInheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, 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
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_019892.6
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.50742 (below the threshold of 3.09). Trascript score misZ: -1.9401 (below the threshold of 3.09). GenCC associations: The gene is linked to Joubert syndrome with ocular defect, MORM syndrome, Joubert syndrome 1, Joubert syndrome, COACH syndrome 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.851
PP5
Variant 9-136430395-T-C is Pathogenic according to our data. Variant chr9-136430395-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217654.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_019892.6. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| INPP5E | TSL:1 MANE Select | c.1684A>G | p.Ser562Gly | missense | Exon 9 of 10 | ENSP00000360777.3 | Q9NRR6-1 | ||
| INPP5E | c.1705A>G | p.Ser569Gly | missense | Exon 9 of 10 | ENSP00000600419.1 | ||||
| INPP5E | c.1681A>G | p.Ser561Gly | missense | Exon 9 of 10 | ENSP00000580949.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1403882Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 692746
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1403882
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
692746
African (AFR)
AF:
AC:
0
AN:
32182
American (AMR)
AF:
AC:
0
AN:
35916
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25196
East Asian (EAS)
AF:
AC:
0
AN:
36884
South Asian (SAS)
AF:
AC:
0
AN:
79582
European-Finnish (FIN)
AF:
AC:
0
AN:
49150
Middle Eastern (MID)
AF:
AC:
0
AN:
5700
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1081084
Other (OTH)
AF:
AC:
0
AN:
58188
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
1
-
-
Joubert syndrome (1)
-
1
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
N
PhyloP100
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of stability (P = 0.0106)
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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