rs11146013

Variant names:

• chr9-136431784-C-T
• rs11146013
• NM_019892.6:c.1549+40G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_019892.6(INPP5E):​c.1549+40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 9)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.323
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 9-136431784-C-T is Benign according to our data. Variant chr9-136431784-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 261198.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1549+40G>A		intron_variant	Intron 7 of 9	ENST00000371712.4	NP_063945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4	c.1549+40G>A		intron_variant	Intron 7 of 9	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1447+40G>A		intron_variant	Intron 7 of 9			ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 14 AN: 58998 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.000358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000203

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.0000637 AC: 10 AN: 157032 AF XY: 0.0000462

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.0000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000802

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000310

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 94 AN: 849992 Hom.: 1 Cov.: 15 AF XY: 0.000107 AC XY: 46 AN XY: 431876

African (AFR) AF: 0.000439 AC: 9 AN: 20512

American (AMR) AF: 0.0000714 AC: 2 AN: 28006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16894

East Asian (EAS) AF: 0.0000457 AC: 1 AN: 21874

South Asian (SAS) AF: 0.0000747 AC: 5 AN: 66966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2900

European-Non Finnish (NFE) AF: 0.000120 AC: 76 AN: 632070

Other (OTH) AF: 0.0000280 AC: 1 AN: 35684

GnomAD4 genome AF: 0.000237 AC: 14 AN: 59020 Hom.: 0 Cov.: 9 AF XY: 0.000179 AC XY: 5 AN XY: 27940

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

African (AFR) AF: 0.000358 AC: 5 AN: 13984

American (AMR) AF: 0.00 AC: 0 AN: 5748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1674

East Asian (EAS) AF: 0.00101 AC: 2 AN: 1986

South Asian (SAS) AF: 0.00 AC: 0 AN: 1312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 134

European-Non Finnish (NFE) AF: 0.000203 AC: 6 AN: 29518

Other (OTH) AF: 0.00143 AC: 1 AN: 698

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000409021), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00185 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.76
PhyloP100		0.32

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: rs11146013; hg19: chr9-139326236; COSMIC: COSV65496458; COSMIC: COSV65496458;