rs11146014

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-136431801-T-A
• chr9-136431801-T-C
• chr9-136431801-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019892.6(INPP5E):​c.1549+23A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 640,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 4)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 43592 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 8 AN: 640440 Hom.: 0 Cov.: 21 AF XY: 0.00000928 AC XY: 3 AN XY: 323214

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

African (AFR) AF: 0.00 AC: 0 AN: 15710

American (AMR) AF: 0.00 AC: 0 AN: 19362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10080

East Asian (EAS) AF: 0.00 AC: 0 AN: 15700

South Asian (SAS) AF: 0.00 AC: 0 AN: 53402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2348

European-Non Finnish (NFE) AF: 0.0000167 AC: 8 AN: 478784

Other (OTH) AF: 0.00 AC: 0 AN: 25556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 43592 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 20730

African (AFR) AF: 0.00 AC: 0 AN: 10604

American (AMR) AF: 0.00 AC: 0 AN: 4532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1024

East Asian (EAS) AF: 0.00 AC: 0 AN: 1436

South Asian (SAS) AF: 0.00 AC: 0 AN: 1030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 98

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 21708

Other (OTH) AF: 0.00 AC: 0 AN: 546

Alfa AF: 0.00 Hom.: 70

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.4
DANN	Benign	0.29
PhyloP100		-2.6

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;