9-136433146-C-CGCGCCCACCCCTCCAGCT

Variant names:

• chr9-136433146-C-CGCGCCCACCCCTCCAGCT
• rs747240016
• NM_019892.6:c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_019892.6(INPP5E):​c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,608,090 control chromosomes in the GnomAD database, including 37 homozygotes. 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 30)
  • Exomes 𝑓: 0.00090 (17 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.284
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 9-136433146-C-CGCGCCCACCCCTCCAGCT is Benign according to our data. Variant chr9-136433146-C-CGCGCCCACCCCTCCAGCT is described in ClinVar as Likely_benign. ClinVar VariationId is 415748.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 = 0.00931 (1413/151724) while in subpopulation AFR AF = 0.0316 (1305/41348). AF 95% confidence interval is 0.0301. There are 20 homozygotes in GnomAd4. There are 691 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

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.1159+8_1159+9insAGCTGGAGGGGTGGGCGC		splice_region intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC		splice_region intron	N/A	NP_001305431.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC		splice_region intron	N/A	ENSP00000360777.3
	INPP5E	ENST00000930360.1		c.1180+8_1180+9insAGCTGGAGGGGTGGGCGC		splice_region intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC		splice_region intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1410 AN: 151606 Hom.: 20 Cov.: 30

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00572

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00823

GnomAD2 exomes AF: 0.00220 AC: 526 AN: 239056 AF XY: 0.00173

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000899 AC: 1309 AN: 1456366 Hom.: 17 Cov.: 42 AF XY: 0.000776 AC XY: 562 AN XY: 724694

African (AFR) AF: 0.0321 AC: 1073 AN: 33456

American (AMR) AF: 0.00199 AC: 89 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48254

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111812

Other (OTH) AF: 0.00209 AC: 126 AN: 60324

GnomAD4 genome AF: 0.00931 AC: 1413 AN: 151724 Hom.: 20 Cov.: 30 AF XY: 0.00932 AC XY: 691 AN XY: 74154

African (AFR) AF: 0.0316 AC: 1305 AN: 41348

American (AMR) AF: 0.00571 AC: 87 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67838

Other (OTH) AF: 0.00814 AC: 17 AN: 2088

Alfa AF: 0.00219 Hom.: 0

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.28
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: rs747240016; hg19: chr9-139327598;