rs73566945

Variant names:

• chr9-136433147-G-A
• rs73566945
• NM_019892.6:c.1159+8C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136433147-G-A
• chr9-136433147-G-C
• chr9-136433147-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019892.6(INPP5E):​c.1159+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,599,200 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Scores: Splicing: ADA: 0.00007583
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.284
• Publications: 22 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• MORM syndrome

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, ClinGen, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-136433147-G-A is Benign according to our data. Variant chr9-136433147-G-A is described in ClinVar as [Benign]. Clinvar id is 129264.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 = 0.00264 (391/148312) while in subpopulation AFR AF = 0.00516 (201/38928). AF 95% confidence interval is 0.00458. There are 1 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1159+8C>T		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000371712.4	NP_063945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4	c.1159+8C>T		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1057+8C>T		splice_region_variant, intron_variant	Intron 4 of 9			ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 391 AN: 148200 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00518

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00167

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00232

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00246

GnomAD4 exome AF: 0.00132 AC: 1916 AN: 1450888 Hom.: 6 Cov.: 42 AF XY: 0.00131 AC XY: 947 AN XY: 722030

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00417 AC: 139 AN: 33360

American (AMR) AF: 0.00295 AC: 131 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.000959 AC: 25 AN: 26062

East Asian (EAS) AF: 0.00303 AC: 120 AN: 39656

South Asian (SAS) AF: 0.000848 AC: 73 AN: 86112

European-Finnish (FIN) AF: 0.00667 AC: 309 AN: 46344

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.000915 AC: 1015 AN: 1108964

Other (OTH) AF: 0.00168 AC: 101 AN: 60150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00264 AC: 391 AN: 148312 Hom.: 1 Cov.: 30 AF XY: 0.00262 AC XY: 190 AN XY: 72424

African (AFR) AF: 0.00516 AC: 201 AN: 38928

American (AMR) AF: 0.00167 AC: 25 AN: 14946

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 7 AN: 3454

East Asian (EAS) AF: 0.00389 AC: 20 AN: 5138

South Asian (SAS) AF: 0.00126 AC: 6 AN: 4778

European-Finnish (FIN) AF: 0.00232 AC: 24 AN: 10356

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 101 AN: 67460

Other (OTH) AF: 0.00243 AC: 5 AN: 2054

Alfa AF: 0.129 Hom.: 11

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Joubert syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.57
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000076
dbscSNV1_RF	Benign	0.0
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: rs73566945; hg19: chr9-139327599; COSMIC: COSV65496129; COSMIC: COSV65496129;