9-136431131-G-A

Variant names:

• chr9-136431131-G-A
• rs181576122
• NM_019892.6:c.1550-14C>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.1550-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,575,526 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (16 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.336
• Publications: 0 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=-0.84).
• BP6: Variant 9-136431131-G-A is Benign according to our data. Variant chr9-136431131-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00124 (187/151408) while in subpopulation AMR AF = 0.00808 (122/15106). AF 95% confidence interval is 0.00691. There are 2 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1550-14C>T		intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1547-14C>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.1550-14C>T		intron	N/A	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.1571-14C>T		intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1547-14C>T		intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 184 AN: 151292 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00789

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00248

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00360 AC: 890 AN: 247214 AF XY: 0.00294

Gnomad AFR exome AF: 0.000441

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000985

Gnomad FIN exome AF: 0.00362

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00100 AC: 1429 AN: 1424118 Hom.: 16 Cov.: 25 AF XY: 0.000919 AC XY: 653 AN XY: 710630

African (AFR) AF: 0.000245 AC: 8 AN: 32706

American (AMR) AF: 0.0184 AC: 814 AN: 44250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00188 AC: 74 AN: 39448

South Asian (SAS) AF: 0.00131 AC: 112 AN: 85346

European-Finnish (FIN) AF: 0.00290 AC: 152 AN: 52396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.000155 AC: 167 AN: 1079278

Other (OTH) AF: 0.00173 AC: 102 AN: 59128

GnomAD4 genome AF: 0.00124 AC: 187 AN: 151408 Hom.: 2 Cov.: 31 AF XY: 0.00149 AC XY: 110 AN XY: 73946

African (AFR) AF: 0.000267 AC: 11 AN: 41250

American (AMR) AF: 0.00808 AC: 122 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5132

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.00248 AC: 26 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67834

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00210 Hom.: 2

Bravo AF: 0.00295

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	INPP5E-related disorder (1)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.38
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs181576122; hg19: chr9-139325583;