rs36064831

Variant names:

• chr9-136438817-G-C
• rs36064831
• NM_019892.6:c.603C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_019892.6(INPP5E):​c.603C>G​(p.Ile201Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,611,706 control chromosomes in the GnomAD database, including 637 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (49 hom., cov: 33)
  • Exomes 𝑓: 0.024 (588 hom.)
• Consequence: INPP5E NM_019892.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.73
• Publications: 11 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: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015648305).
• BP6: Variant 9-136438817-G-C is Benign according to our data. Variant chr9-136438817-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

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.603C>G	p.Ile201Met	missense	Exon 1 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.603C>G	p.Ile201Met	missense	Exon 1 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.603C>G	p.Ile201Met	missense	Exon 1 of 10	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.603C>G	p.Ile201Met	missense	Exon 1 of 10	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.603C>G	p.Ile201Met	missense	Exon 1 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2826 AN: 152180 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0204 AC: 4912 AN: 241276 AF XY: 0.0208

Gnomad AFR exome AF: 0.00613

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00411

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0236 AC: 34444 AN: 1459408 Hom.: 588 Cov.: 35 AF XY: 0.0237 AC XY: 17171 AN XY: 725974

African (AFR) AF: 0.00744 AC: 249 AN: 33454

American (AMR) AF: 0.0186 AC: 831 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2817 AN: 26082

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39674

South Asian (SAS) AF: 0.00888 AC: 765 AN: 86162

European-Finnish (FIN) AF: 0.00537 AC: 279 AN: 51910

Middle Eastern (MID) AF: 0.0715 AC: 412 AN: 5764

European-Non Finnish (NFE) AF: 0.0246 AC: 27372 AN: 1111466

Other (OTH) AF: 0.0284 AC: 1715 AN: 60306

GnomAD4 genome AF: 0.0185 AC: 2825 AN: 152298 Hom.: 49 Cov.: 33 AF XY: 0.0184 AC XY: 1370 AN XY: 74466

African (AFR) AF: 0.00601 AC: 250 AN: 41576

American (AMR) AF: 0.0258 AC: 395 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 386 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00827 AC: 40 AN: 4834

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10626

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0237 AC: 1609 AN: 68000

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

Alfa AF: 0.0309 Hom.: 48

Bravo AF: 0.0217

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00592 AC: 26

ESP6500EA AF: 0.0300 AC: 258

ExAC AF: 0.0187 AC: 2256

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.50
DANN	Benign	0.71
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-1.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.21
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.033	B
Vest4		0.011
MPC		0.33
ClinPred		0.0044	T
GERP RS		-6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.36
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs36064831; hg19: chr9-139333269; COSMIC: COSV51521141; COSMIC: COSV51521141;