rs863225197

Positions:

• chr9-136430395-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

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).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INPP5E NM_019892.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 217654.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr9-136430395-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1684A>G	p.Ser562Gly	missense_variant	9/10	ENST00000371712.4	NP_063945.2
INPP5E	NM_001318502.2	c.1681A>G	p.Ser561Gly	missense_variant	9/10		NP_001305431.1
INPP5E	XM_017014926.2	c.1684A>G	p.Ser562Gly	missense_variant	9/10		XP_016870415.1
INPP5E	XM_047423603.1	c.1681A>G	p.Ser561Gly	missense_variant	9/10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4	c.1684A>G	p.Ser562Gly	missense_variant	9/10	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1582A>G	p.Ser528Gly	missense_variant	9/10			ENSP00000501984.1
INPP5E	ENST00000674693.1	n.201A>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403882 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 692746

Gnomad4 AFR exome AF: 0.00

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 Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial aplasia of the vermis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2021

Previously identified in individuals with Joubert syndrome who harbored a second INPP5E variant, however segregation to determine the phase of the variants was not reported (Bachmann-Gagescu et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26092869) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	0.71	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.74
Sift	Benign	0.17	T
Sift4G	Uncertain	0.028	D
Polyphen		0.90	P
Vest4		0.85
MutPred		0.49		Loss of stability (P = 0.0106);
MVP		0.97
MPC		0.69
ClinPred		0.88	D
GERP RS		5.2
Varity_R		0.67
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs863225197; hg19: chr9-139324847;