17-1496119-GAA-G

Position:

• chr17-1496119-GAA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_016532.4(INPP5K):​c.1229_1230delTT​(p.Phe410fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: INPP5K NM_016532.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.39

Genes affected

INPP5K (HGNC:33882): (inositol polyphosphate-5-phosphatase K) This gene encodes a protein with 5-phosphatase activity toward polyphosphate inositol. The protein localizes to the cytosol in regions lacking actin stress fibers. It is thought that this protein may negatively regulate the actin cytoskeleton. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

INPP5K (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0876 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-1496119-GAA-G is Pathogenic according to our data. Variant chr17-1496119-GAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2227818.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5K	NM_016532.4	c.1229_1230delTT	p.Phe410fs	frameshift_variant	11/12	ENST00000421807.7	NP_057616.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5K	ENST00000421807.7	c.1229_1230delTT	p.Phe410fs	frameshift_variant	11/12	1	NM_016532.4	ENSP00000413937.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2020

The c.1229_1230delTT (p.F410Sfs*33) alteration, located in coding exon 11 of the INPP5K gene, consists of a deletion of 2 nucleotides from position 1229 to 1230, causing a translational frameshift with a predicted alternate stop codon after 33 amino acids. This alteration occurs at the 3' terminus of the INPP5K gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 9% of the protein. However, premature stop codons are typically deleterious in nature, an additional frameshift alteration downstream of this alteration has been reported in the literature as disease-causing, and the impacted region is critical for protein function (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD), the INPP5K c.1229_1230delTT alteration was not observed, with coverage at this position. A downstream frameshift alteration, c.1251_1252delCA (p.Asn417Lysfs*26), with the same reading frameshift has been described in trans with a second alteration in a patient with features consistent with INPP5K-related muscular dystrophy with cataracts. Phosphatase activity assays observed protein function from this alteration was 57% of wild type function (Osborn, 2017). Based on internal structural analysis, the c.1229_1230delTT (p.F410Sfs*33) alteration involves the region between amino acid positions 318-448, which is required for interaction with GPR78 and Pak1 based on UniPro database (Ijuin, 2016). This alteration interrupts ~28% of the protein-protein binding region and is predicted to disrupt protein-protein interaction. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-1399413;