rs5901103

Variant names:

• chr9-136438597-GCCCT-G
• rs5901103
• NM_019892.6:c.812+7_812+10delAGGG

Your query was ambiguous. Multiple possible variants found:

• chr9-136438597-GCCCT-G
• chr9-136438597-GCCCT-GCCCTCCCT

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.812+7_812+10delAGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,550,996 control chromosomes in the GnomAD database, including 667,162 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67416 hom., cov: 0)
  • Exomes 𝑓: 0.93 (599746 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 1.21
• 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 9-136438597-GCCCT-G is Benign according to our data. Variant chr9-136438597-GCCCT-G is described in ClinVar as Benign. ClinVar VariationId is 261203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.812+7_812+10delAGGG		splice_region intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.812+7_812+10delAGGG		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.812+7_812+10delAGGG		splice_region intron	N/A	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.812+7_812+10delAGGG		splice_region intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.812+7_812+10delAGGG		splice_region intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.941 AC: 143010 AN: 151978 Hom.: 67351 Cov.: 0

Gnomad AFR AF: 0.985

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.948

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.921

Gnomad OTH AF: 0.924

GnomAD2 exomes AF: 0.934 AC: 139958 AN: 149796 AF XY: 0.932

Gnomad AFR exome AF: 0.988

Gnomad AMR exome AF: 0.961

Gnomad ASJ exome AF: 0.915

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.889

Gnomad NFE exome AF: 0.922

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.926 AC: 1294939 AN: 1398902 Hom.: 599746 AF XY: 0.926 AC XY: 639123 AN XY: 690482

African (AFR) AF: 0.988 AC: 31285 AN: 31678

American (AMR) AF: 0.959 AC: 34491 AN: 35980

Ashkenazi Jewish (ASJ) AF: 0.915 AC: 23031 AN: 25180

East Asian (EAS) AF: 1.00 AC: 36049 AN: 36060

South Asian (SAS) AF: 0.929 AC: 73983 AN: 79596

European-Finnish (FIN) AF: 0.892 AC: 42837 AN: 48042

Middle Eastern (MID) AF: 0.867 AC: 4426 AN: 5104

European-Non Finnish (NFE) AF: 0.922 AC: 995065 AN: 1079306

Other (OTH) AF: 0.928 AC: 53772 AN: 57956

GnomAD4 genome AF: 0.941 AC: 143134 AN: 152094 Hom.: 67416 Cov.: 0 AF XY: 0.940 AC XY: 69869 AN XY: 74338

African (AFR) AF: 0.985 AC: 40933 AN: 41544

American (AMR) AF: 0.948 AC: 14494 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 3188 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5145 AN: 5148

South Asian (SAS) AF: 0.935 AC: 4512 AN: 4828

European-Finnish (FIN) AF: 0.886 AC: 9376 AN: 10578

Middle Eastern (MID) AF: 0.862 AC: 250 AN: 290

European-Non Finnish (NFE) AF: 0.921 AC: 62554 AN: 67930

Other (OTH) AF: 0.926 AC: 1953 AN: 2110

Alfa AF: 0.935 Hom.: 12017

Bravo AF: 0.946

Asia WGS AF: 0.969 AC: 3366 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs5901103; hg19: chr9-139333049; COSMIC: COSV107319344; COSMIC: COSV107319344;