Variant chr9-136429689-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_019892.6(INPP5E):c.1921T>G(p.Cys641Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,254 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C641R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

INPP5E
NM_019892.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.71

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 Pathogenic. Variant got 10 ACMG points.

PM1

In a modified_residue Cysteine methyl ester (size 0) in uniprot entity INP5E_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1921T>G	p.Cys641Gly	missense_variant	10/10	ENST00000371712.4	NP_063945.2	Q9NRR6-1
INPP5E	NM_001318502.2 link	c.1918T>G	p.Cys640Gly	missense_variant	10/10		NP_001305431.1	Q9NRR6
INPP5E	XM_017014926.2 link	c.*65T>G		3_prime_UTR_variant	10/10		XP_016870415.1
INPP5E	XM_047423603.1 link	c.*65T>G		3_prime_UTR_variant	10/10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4 link	c.1921T>G	p.Cys641Gly	missense_variant	10/10	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1819T>G	p.Cys607Gly	missense_variant	10/10			ENSP00000501984.1		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74384

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MORM syndrome;C4551568:Joubert syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-9.6

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MVP

0.98

MPC

1.2

ClinPred

1.0

GERP RS

5.5

Varity_R

0.92

gMVP

0.78

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over