chr9-136433147-G-GCGCCCACCCCTCCAGCCA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_019892.6(INPP5E):​c.1159+7_1159+8insTGGCTGGAGGGGTGGGCG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 147,718 control chromosomes in the GnomAD database, including 5,144 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 0.26 (5144 hom., cov: 28)
  • Exomes 𝑓: 0.29 (63852 hom.)
  • Failed GnomAD Quality Control
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• 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-GCGCCCACCCCTCCAGCCA is Benign according to our data. Variant chr9-136433147-G-GCGCCCACCCCTCCAGCCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

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+8insTGGCTGGAGGGGTGGGCG		splice_region intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1159+7_1159+8insTGGCTGGAGGGGTGGGCG		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+8insTGGCTGGAGGGGTGGGCG		splice_region intron	N/A	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.1180+7_1180+8insTGGCTGGAGGGGTGGGCG		splice_region intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1159+7_1159+8insTGGCTGGAGGGGTGGGCG		splice_region intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 38034 AN: 147600 Hom.: 5142 Cov.: 28

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.0447

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.263

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.289 AC: 417440 AN: 1443622 Hom.: 63852 Cov.: 53 AF XY: 0.285 AC XY: 204963 AN XY: 718522

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

African (AFR) AF: 0.187 AC: 6224 AN: 33230

American (AMR) AF: 0.283 AC: 12533 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6558 AN: 25930

East Asian (EAS) AF: 0.0762 AC: 3014 AN: 39548

South Asian (SAS) AF: 0.170 AC: 14655 AN: 86004

European-Finnish (FIN) AF: 0.276 AC: 12748 AN: 46118

Middle Eastern (MID) AF: 0.187 AC: 1069 AN: 5720

European-Non Finnish (NFE) AF: 0.313 AC: 344694 AN: 1102892

Other (OTH) AF: 0.267 AC: 15945 AN: 59824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.258 AC: 38065 AN: 147718 Hom.: 5144 Cov.: 28 AF XY: 0.252 AC XY: 18158 AN XY: 72098

African (AFR) AF: 0.196 AC: 7587 AN: 38758

American (AMR) AF: 0.286 AC: 4242 AN: 14840

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 854 AN: 3454

East Asian (EAS) AF: 0.0446 AC: 229 AN: 5134

South Asian (SAS) AF: 0.163 AC: 778 AN: 4762

European-Finnish (FIN) AF: 0.277 AC: 2838 AN: 10250

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20677 AN: 67270

Other (OTH) AF: 0.263 AC: 541 AN: 2054

Alfa AF: 0.209 Hom.: 959

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Joubert syndrome (2)
-	-	2	not provided (2)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV65496119; COSMIC: COSV65496119;