9-136433073-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_019892.6(INPP5E):c.1162G>A(p.Val388Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000124 in 1,611,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V388L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

INPP5E
NM_019892.6 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.51

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]

INPP5E links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_019892.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-136433073-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217663.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.1162G>A	p.Val388Met	missense_variant, splice_region_variant	5/10	ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4 linkuse as main transcript	c.1162G>A	p.Val388Met	missense_variant, splice_region_variant	5/10	1	NM_019892.6	P1	Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1060G>A	p.Val354Met	missense_variant, splice_region_variant	5/10				Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460764

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150760

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73640

show subpopulations

Gnomad4 AFR

AF:

0.0000249

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.83

Sift

Uncertain

0.011

Sift4G

Uncertain

0.030

Polyphen

0.84

Vest4

0.67

MutPred

0.64

Gain of catalytic residue at V388 (P = 0.0626);

MVP

0.98

MPC

1.0

ClinPred

0.95

GERP RS

4.8

Varity_R

0.37

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over