9-136431801-T-C

Variant names:

• chr9-136431801-T-C
• rs11146014
• NM_019892.6:c.1549+23A>G

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.1549+23A>G 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (1901 hom., cov: 4)
  • Exomes 𝑓: 0.19 (14310 hom.)
  • Failed GnomAD Quality Control
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.60
• Publications: 10 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=-0.96).
• BP6: Variant 9-136431801-T-C is Benign according to our data. Variant chr9-136431801-T-C is described in ClinVar as Benign. ClinVar VariationId is 261197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1549+23A>G		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+23A>G		intron_variant	Intron 7 of 9	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1447+23A>G		intron_variant	Intron 7 of 9			ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 12719 AN: 43248 Hom.: 1904 Cov.: 4

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.391

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.163 AC: 17607 AN: 107742 AF XY: 0.151

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.222

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.194 AC: 123121 AN: 635166 Hom.: 14310 Cov.: 21 AF XY: 0.191 AC XY: 61204 AN XY: 320558

African (AFR) AF: 0.169 AC: 2616 AN: 15482

American (AMR) AF: 0.143 AC: 2729 AN: 19056

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 2308 AN: 9916

East Asian (EAS) AF: 0.209 AC: 3194 AN: 15318

South Asian (SAS) AF: 0.110 AC: 5837 AN: 52966

European-Finnish (FIN) AF: 0.240 AC: 4642 AN: 19342

Middle Eastern (MID) AF: 0.115 AC: 267 AN: 2328

European-Non Finnish (NFE) AF: 0.202 AC: 96228 AN: 475448

Other (OTH) AF: 0.209 AC: 5300 AN: 25310

GnomAD4 genome AF: 0.294 AC: 12717 AN: 43262 Hom.: 1901 Cov.: 4 AF XY: 0.279 AC XY: 5741 AN XY: 20610

African (AFR) AF: 0.258 AC: 2714 AN: 10530

American (AMR) AF: 0.280 AC: 1267 AN: 4520

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 289 AN: 1014

East Asian (EAS) AF: 0.180 AC: 256 AN: 1420

South Asian (SAS) AF: 0.222 AC: 225 AN: 1014

European-Finnish (FIN) AF: 0.328 AC: 774 AN: 2362

Middle Eastern (MID) AF: 0.390 AC: 32 AN: 82

European-Non Finnish (NFE) AF: 0.321 AC: 6924 AN: 21540

Other (OTH) AF: 0.260 AC: 144 AN: 554

Alfa AF: 0.124 Hom.: 70

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: 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	-0.96
CADD	Benign	1.9
DANN	Benign	0.16
PhyloP100		-2.6
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: rs11146014; hg19: chr9-139326253; COSMIC: COSV65496968; COSMIC: COSV65496968;