NM_019892.6:c.33C>G

Variant names:

• chr9-136439387-G-C
• rs79161998
• NM_019892.6:c.33C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019892.6(INPP5E):​c.33C>G​(p.Ser11Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,463,608 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S11S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (168 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (104 hom.)
• Consequence: INPP5E NM_019892.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.44
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-136439387-G-C is Benign according to our data. Variant chr9-136439387-G-C is described in ClinVar as Benign. ClinVar VariationId is 129273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.075 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	NM_019892.6	MANE Select	c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	NP_001305431.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	ENSP00000360777.3
	INPP5E	ENST00000676019.1		c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	ENSP00000501984.1
	INPP5E	ENST00000635815.1	TSL:6	n.437C>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3475 AN: 152020 Hom.: 168 Cov.: 33

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00231 AC: 173 AN: 74920 AF XY: 0.00168

Gnomad AFR exome AF: 0.0855

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00685

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00244 AC: 3200 AN: 1311480 Hom.: 104 Cov.: 34 AF XY: 0.00216 AC XY: 1395 AN XY: 645926

African (AFR) AF: 0.0839 AC: 2223 AN: 26498

American (AMR) AF: 0.00480 AC: 119 AN: 24804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23030

East Asian (EAS) AF: 0.00338 AC: 98 AN: 28996

South Asian (SAS) AF: 0.000354 AC: 25 AN: 70530

European-Finnish (FIN) AF: 0.0000601 AC: 2 AN: 33276

Middle Eastern (MID) AF: 0.00592 AC: 23 AN: 3884

European-Non Finnish (NFE) AF: 0.000262 AC: 274 AN: 1046070

Other (OTH) AF: 0.00802 AC: 436 AN: 54392

GnomAD4 genome AF: 0.0229 AC: 3478 AN: 152128 Hom.: 168 Cov.: 33 AF XY: 0.0219 AC XY: 1630 AN XY: 74376

African (AFR) AF: 0.0773 AC: 3208 AN: 41522

American (AMR) AF: 0.0106 AC: 162 AN: 15294

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

East Asian (EAS) AF: 0.00485 AC: 25 AN: 5158

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67958

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00406 Hom.: 2

Bravo AF: 0.0260

Asia WGS AF: 0.0120 AC: 40 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Joubert syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Joubert syndrome 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		-3.4
PromoterAI		-0.036	Neutral
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: rs79161998; hg19: chr9-139333839;