5-68295418-AGGT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePM2PP3_ModeratePP5

The NM_181523.3(PIK3R1):​c.1748_1750del​(p.Trp583del) variant causes a splice acceptor, coding sequence change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3R1
NM_181523.3 splice_acceptor, coding_sequence

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
PIK3R1 (HGNC:8979): (phosphoinositide-3-kinase regulatory subunit 1) Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03126437 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9, offset of 0 (no position change), new splice context is: ttttcaaaactgtttttcAGgtt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 5-68295418-AGGT-A is Pathogenic according to our data. Variant chr5-68295418-AGGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376263.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-68295418-AGGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PIK3R1NM_181523.3 linkuse as main transcriptc.1748_1750del p.Trp583del splice_acceptor_variant, coding_sequence_variant 14/16 ENST00000521381.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PIK3R1ENST00000521381.6 linkuse as main transcriptc.1748_1750del p.Trp583del splice_acceptor_variant, coding_sequence_variant 14/161 NM_181523.3 P1P27986-1

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Jul 14, 2015- -
Vascular Malformations and Overgrowth Pathogenic:1
Pathogenic, no assertion criteria providedresearchInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalNov 08, 2020This alteration is of apparent somatic mosaic etiology with strong supporting evidence including no discernible strand bias, in a region absent of repetition and sequence homology, with clean, high-quality reads, having a variant allele fraction >= 3% [PS2], is supported by well-established models demonstrating downstream impact of the variant on RNA structure, gene expression, or protein function [PS3], is either well-represented in cancer as identified in the COSMIC database with >=20 documented instances or considered to occur in a statistically significant hotspot or region according to cancerhotspots.org database [PM_CANCER], is in a non-repetitive region and results in a protein length change predicted to result in an in-frame protein product [PM4], and is at increased prevalence in our cohort, with >= 3 occurrences in unrelated individuals [PS4_Sup]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
1.0
Position offset: 5
DS_AL_spliceai
1.0
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1131692243; hg19: chr5-67591246; API