9-136433147-G-GCGCCCACCCCTCTAGCCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_019892.6(INPP5E):c.1159+7_1159+8insTGGCTAGAGGGGTGGGCG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,600,660 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 6 hom., cov: 28)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

INPP5E
NM_019892.6 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.695

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 was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 9-136433147-G-GCGCCCACCCCTCTAGCCA is Benign according to our data. Variant chr9-136433147-G-GCGCCCACCCCTCTAGCCA is described in ClinVar as [Benign]. Clinvar id is 695325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00507 (753/148454) while in subpopulation AFR AF = 0.0183 (714/38956). AF 95% confidence interval is 0.0172. There are 6 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1159+7_1159+8insTGGCTAGAGGGGTGGGCG		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000371712.4	NP_063945.2	Q9NRR6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4 link	c.1159+7_1159+8insTGGCTAGAGGGGTGGGCG		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1057+7_1057+8insTGGCTAGAGGGGTGGGCG		splice_region_variant, intron_variant	Intron 4 of 9			ENSP00000501984.1		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.00505

AC:

749

AN:

148340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00181

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000888

Gnomad OTH

AF:

0.00197

GnomAD4 exome

AF:

0.000585

AC:

849

AN:

1452206

Hom.:

Cov.:

AF XY:

0.000516

AC XY:

373

AN XY:

722666

show subpopulations

Gnomad4 AFR exome

AF:

0.0181

AC:

605

AN:

33390

Gnomad4 AMR exome

AF:

0.00162

AC:

AN:

44508

Gnomad4 ASJ exome

AF:

0.000537

AC:

AN:

26078

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39662

Gnomad4 SAS exome

AF:

0.0000232

AC:

AN:

86154

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

46438

Gnomad4 NFE exome

AF:

0.0000667

AC:

AN:

1110024

Gnomad4 Remaining exome

AF:

0.00126

AC:

AN:

60192

Heterozygous variant carriers

137

182

228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00507

AC:

753

AN:

148454

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

337

AN XY:

72510

show subpopulations

Gnomad4 AFR

AF:

0.0183

AC:

0.0183284

AN:

0.0183284

Gnomad4 AMR

AF:

0.00180

AC:

0.00180481

AN:

0.00180481

Gnomad4 ASJ

AF:

0.000289

AC:

0.000289352

AN:

0.000289352

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000209

AC:

0.000209118

AN:

0.000209118

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000888

AC:

0.0000888494

AN:

0.0000888494

Gnomad4 OTH

AF:

0.00195

AC:

0.00194742

AN:

0.00194742

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000207

Hom.:

959

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

May 17, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joubert syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism

Splicing

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