9-136433147-G-A

Variant names:

• chr9-136433147-G-A
• rs73566945
• NM_019892.6:c.1159+8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019892.6(INPP5E):​c.1159+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,599,200 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Scores: Splicing: ADA: 0.00007583
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.284
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-136433147-G-A is Benign according to our data. Variant chr9-136433147-G-A is described in ClinVar as Benign. ClinVar VariationId is 129264.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 = 0.00264 (391/148312) while in subpopulation AFR AF = 0.00516 (201/38928). AF 95% confidence interval is 0.00458. There are 1 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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+8C>T		splice_region intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1159+8C>T		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+8C>T		splice_region intron	N/A	ENSP00000360777.3
	INPP5E	ENST00000930360.1		c.1180+8C>T		splice_region intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1159+8C>T		splice_region intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 391 AN: 148200 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00518

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00167

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00232

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00246

GnomAD4 exome AF: 0.00132 AC: 1916 AN: 1450888 Hom.: 6 Cov.: 42 AF XY: 0.00131 AC XY: 947 AN XY: 722030

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

African (AFR) AF: 0.00417 AC: 139 AN: 33360

American (AMR) AF: 0.00295 AC: 131 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.000959 AC: 25 AN: 26062

East Asian (EAS) AF: 0.00303 AC: 120 AN: 39656

South Asian (SAS) AF: 0.000848 AC: 73 AN: 86112

European-Finnish (FIN) AF: 0.00667 AC: 309 AN: 46344

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.000915 AC: 1015 AN: 1108964

Other (OTH) AF: 0.00168 AC: 101 AN: 60150

⚠️ 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: 0.00264 AC: 391 AN: 148312 Hom.: 1 Cov.: 30 AF XY: 0.00262 AC XY: 190 AN XY: 72424

African (AFR) AF: 0.00516 AC: 201 AN: 38928

American (AMR) AF: 0.00167 AC: 25 AN: 14946

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 7 AN: 3454

East Asian (EAS) AF: 0.00389 AC: 20 AN: 5138

South Asian (SAS) AF: 0.00126 AC: 6 AN: 4778

European-Finnish (FIN) AF: 0.00232 AC: 24 AN: 10356

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 101 AN: 67460

Other (OTH) AF: 0.00243 AC: 5 AN: 2054

Alfa AF: 0.129 Hom.: 11

ClinVar

ClinVar submissions as Germline

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)
-	-	1	Joubert syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.57
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000076
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs73566945; hg19: chr9-139327599; COSMIC: COSV65496129; COSMIC: COSV65496129;