chr9-136433147-G-GCGCCCACCCCTCCAGCCGCGCCCACCCCTCCAGCCGCGCCCACCCCTCCAGCCA

Variant names:

• chr9-136433147-G-GCGCCCACCCCTCCAGCCGCGCCCACCCCTCCAGCCGCGCCCACCCCTCCAGCCA
• rs71269007
• NM_019892.6:c.1159+7_1159+8insTGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_019892.6(INPP5E):​c.1159+7_1159+8insTGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,452,132 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 28)
  • Exomes 𝑓: 0.000074 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.695
• Publications: 8 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1159+7_1159+8insTGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCG		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+7_1159+8insTGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCG		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1057+7_1057+8insTGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCGCGGCTGGAGGGGTGGGCG		splice_region_variant, intron_variant	Intron 4 of 9			ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.000229 AC: 34 AN: 148346 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.000438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000669

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000737 AC: 107 AN: 1452132 Hom.: 0 Cov.: 53 AF XY: 0.0000789 AC XY: 57 AN XY: 722628

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

African (AFR) AF: 0.000150 AC: 5 AN: 33396

American (AMR) AF: 0.0000899 AC: 4 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.000499 AC: 13 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.0000215 AC: 1 AN: 46438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000703 AC: 78 AN: 1109958

Other (OTH) AF: 0.0000997 AC: 6 AN: 60192

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000229 AC: 34 AN: 148460 Hom.: 1 Cov.: 28 AF XY: 0.000179 AC XY: 13 AN XY: 72516

African (AFR) AF: 0.000436 AC: 17 AN: 38964

American (AMR) AF: 0.0000669 AC: 1 AN: 14958

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67530

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.0000691 Hom.: 959

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71269007; hg19: chr9-139327599;