chr9-136430228-C-T

Variant names:

• chr9-136430228-C-T
• rs4451431
• NM_019892.6:c.1802+49G>A

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.1802+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,548,680 control chromosomes in the GnomAD database, including 18,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1962 hom., cov: 33)
  • Exomes 𝑓: 0.15 (16312 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.126
• 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=-0.85).
• BP6: Variant 9-136430228-C-T is Benign according to our data. Variant chr9-136430228-C-T is described in ClinVar as Benign. ClinVar VariationId is 261200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.217 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.1802+49G>A		intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1799+49G>A		intron	N/A	NP_001305431.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1802+49G>A		intron	N/A	ENSP00000360777.3
	INPP5E	ENST00000676019.1		c.1700+49G>A		intron	N/A	ENSP00000501984.1
	INPP5E	ENST00000674693.1		n.*107G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23435 AN: 152092 Hom.: 1948 Cov.: 33

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0732

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.161 AC: 24945 AN: 154834 AF XY: 0.156

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.0688

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.149 AC: 208116 AN: 1396470 Hom.: 16312 Cov.: 32 AF XY: 0.149 AC XY: 102456 AN XY: 688700

African (AFR) AF: 0.176 AC: 5542 AN: 31578

American (AMR) AF: 0.272 AC: 9699 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2887 AN: 25156

East Asian (EAS) AF: 0.135 AC: 4812 AN: 35728

South Asian (SAS) AF: 0.163 AC: 12888 AN: 79198

European-Finnish (FIN) AF: 0.0736 AC: 3511 AN: 47706

Middle Eastern (MID) AF: 0.132 AC: 743 AN: 5640

European-Non Finnish (NFE) AF: 0.148 AC: 159456 AN: 1077862

Other (OTH) AF: 0.148 AC: 8578 AN: 57924

GnomAD4 genome AF: 0.154 AC: 23488 AN: 152210 Hom.: 1962 Cov.: 33 AF XY: 0.152 AC XY: 11310 AN XY: 74418

African (AFR) AF: 0.177 AC: 7366 AN: 41534

American (AMR) AF: 0.223 AC: 3417 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 430 AN: 3470

East Asian (EAS) AF: 0.148 AC: 763 AN: 5164

South Asian (SAS) AF: 0.157 AC: 757 AN: 4826

European-Finnish (FIN) AF: 0.0732 AC: 777 AN: 10612

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9540 AN: 67980

Other (OTH) AF: 0.154 AC: 326 AN: 2114

Alfa AF: 0.146 Hom.: 715

Bravo AF: 0.169

Asia WGS AF: 0.166 AC: 579 AN: 3478

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.59
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4451431; hg19: chr9-139324680; COSMIC: COSV65496031;