chr9-136433129-G-A

Variant names:

• chr9-136433129-G-A
• rs140797474
• NM_019892.6:c.1159+26C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019892.6(INPP5E):​c.1159+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,608,534 control chromosomes in the GnomAD database, including 498 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 34)
  • Exomes 𝑓: 0.021 (458 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.47
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 9-136433129-G-A is Benign according to our data. Variant chr9-136433129-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0554 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+26C>T		intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1159+26C>T		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+26C>T		intron	N/A	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.1180+26C>T		intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1159+26C>T		intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2485 AN: 151474 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.0287

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0274

GnomAD2 exomes AF: 0.0184 AC: 4496 AN: 244508 AF XY: 0.0189

Gnomad AFR exome AF: 0.00568

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0800

Gnomad EAS exome AF: 0.000605

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0212 AC: 30908 AN: 1456942 Hom.: 458 Cov.: 55 AF XY: 0.0212 AC XY: 15387 AN XY: 724940

African (AFR) AF: 0.00545 AC: 182 AN: 33410

American (AMR) AF: 0.0179 AC: 802 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 2091 AN: 26108

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39664

South Asian (SAS) AF: 0.00827 AC: 713 AN: 86234

European-Finnish (FIN) AF: 0.00379 AC: 189 AN: 49888

Middle Eastern (MID) AF: 0.0607 AC: 350 AN: 5768

European-Non Finnish (NFE) AF: 0.0226 AC: 25083 AN: 1110912

Other (OTH) AF: 0.0247 AC: 1489 AN: 60268

GnomAD4 genome AF: 0.0164 AC: 2484 AN: 151592 Hom.: 40 Cov.: 34 AF XY: 0.0162 AC XY: 1200 AN XY: 74130

African (AFR) AF: 0.00522 AC: 215 AN: 41164

American (AMR) AF: 0.0245 AC: 374 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 281 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00685 AC: 33 AN: 4818

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10614

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0215 AC: 1455 AN: 67814

Other (OTH) AF: 0.0271 AC: 57 AN: 2106

Alfa AF: 0.0296 Hom.: 14

Bravo AF: 0.0212

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.028
DANN	Benign	0.69
PhyloP100		-3.5
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: rs140797474; hg19: chr9-139327581;