NM_019892.6:c.1304G>A

Variant names:

• chr9-136432562-C-T
• rs121918129
• NM_019892.6:c.1304G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_019892.6(INPP5E):​c.1304G>A​(p.Arg435Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,397,798 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. R435W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: INPP5E NM_019892.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.39
• Publications: 9 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 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• MORM syndrome

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, Orphanet
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-136432563-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 375472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.993
• PP5: Variant 9-136432562-C-T is Pathogenic according to our data. Variant chr9-136432562-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	NM_019892.6	MANE Select	c.1304G>A	p.Arg435Gln	missense	Exon 6 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.1301G>A	p.Arg434Gln	missense	Exon 6 of 10	NP_001305431.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1304G>A	p.Arg435Gln	missense	Exon 6 of 10	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.1325G>A	p.Arg442Gln	missense	Exon 6 of 10	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1301G>A	p.Arg434Gln	missense	Exon 6 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000320 AC: 5 AN: 156220 AF XY: 0.0000243

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000828

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 26 AN: 1397798 Hom.: 0 Cov.: 32 AF XY: 0.0000189 AC XY: 13 AN XY: 689494

African (AFR) AF: 0.00 AC: 0 AN: 31620

American (AMR) AF: 0.00 AC: 0 AN: 35734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35886

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000195 AC: 21 AN: 1078612

Other (OTH) AF: 0.0000172 AC: 1 AN: 57974

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000204 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000124 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Joubert syndrome 1 (3)
2	-	-	Joubert syndrome (2)
1	-	-	INPP5E-related disorder (1)
1	-	-	MORM syndrome;C4551568:Joubert syndrome 1 (1)
1	-	-	not provided (1)
1	-	-	not specified (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Gain of ubiquitination at K431 (P = 0.0577)
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121918129; hg19: chr9-139327014; COSMIC: COSV104684277; COSMIC: COSV104684277;