9-136433147-G-GCGCCCACCCCTCTAGCCA

Variant names:

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

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+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. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 28)
  • Exomes 𝑓: 0.00058 (2 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: 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 -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 VariationId 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 passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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+7_1159+8insTGGCTAGAGGGGTGGGCG		splice_region intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1159+7_1159+8insTGGCTAGAGGGGTGGGCG		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+7_1159+8insTGGCTAGAGGGGTGGGCG		splice_region intron	N/A	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.1180+7_1180+8insTGGCTAGAGGGGTGGGCG		splice_region intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1159+7_1159+8insTGGCTAGAGGGGTGGGCG		splice_region intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 749 AN: 148340 Hom.: 6 Cov.: 28

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.: 2 Cov.: 53 AF XY: 0.000516 AC XY: 373 AN XY: 722666

African (AFR) AF: 0.0181 AC: 605 AN: 33390

American (AMR) AF: 0.00162 AC: 72 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.000537 AC: 14 AN: 26078

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46438

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5760

European-Non Finnish (NFE) AF: 0.0000667 AC: 74 AN: 1110024

Other (OTH) AF: 0.00126 AC: 76 AN: 60192

GnomAD4 genome AF: 0.00507 AC: 753 AN: 148454 Hom.: 6 Cov.: 28 AF XY: 0.00465 AC XY: 337 AN XY: 72510

African (AFR) AF: 0.0183 AC: 714 AN: 38956

American (AMR) AF: 0.00180 AC: 27 AN: 14960

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3456

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

South Asian (SAS) AF: 0.000209 AC: 1 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: 0.0000888 AC: 6 AN: 67530

Other (OTH) AF: 0.00195 AC: 4 AN: 2054

Alfa AF: 0.000207 Hom.: 959

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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;