rs79161998

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-136439387-G-A
• chr9-136439387-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_019892.6(INPP5E):​c.33C>T​(p.Ser11Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,311,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S11S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: INPP5E NM_019892.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-136439387-G-A is Benign according to our data. Variant chr9-136439387-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 517105.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.43 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.33C>T	p.Ser11Ser	synonymous_variant	Exon 1 of 10	ENST00000371712.4	NP_063945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4	c.33C>T	p.Ser11Ser	synonymous_variant	Exon 1 of 10	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.33C>T	p.Ser11Ser	synonymous_variant	Exon 1 of 10			ENSP00000501984.1
INPP5E	ENST00000635815.1	n.437C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1311486 Hom.: 0 Cov.: 34 AF XY: 0.00000310 AC XY: 2 AN XY: 645930

African (AFR) AF: 0.00 AC: 0 AN: 26500

American (AMR) AF: 0.00 AC: 0 AN: 24804

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 28996

South Asian (SAS) AF: 0.0000284 AC: 2 AN: 70532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3884

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1046072

Other (OTH) AF: 0.00 AC: 0 AN: 54392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 27, 2018

GeneDx

Significance: Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.5
DANN	Benign	0.96
PhyloP100		-3.4
PromoterAI		-0.0032	Neutral

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;