rs61761068
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_001142633.3(PIK3R5):c.1885C>T(p.Pro629Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00152 in 1,614,038 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0079 ( 17 hom., cov: 32)
Exomes 𝑓: 0.00086 ( 13 hom. )
Consequence
PIK3R5
NM_001142633.3 missense
NM_001142633.3 missense
Scores
1
5
12
Clinical Significance
Conservation
PhyloP100: 6.31
Genes affected
PIK3R5 (HGNC:30035): (phosphoinositide-3-kinase regulatory subunit 5) Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory subunit of the class I PI3K gamma complex, which is a dimeric enzyme, consisting of a 110 kD catalytic subunit gamma and a regulatory subunit of either 55, 87 or 101 kD. This protein recruits the catalytic subunit from the cytosol to the plasma membrane through high-affinity interaction with G-beta-gamma proteins. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found. [provided by RefSeq, Oct 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.008457243).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00791 (1205/152308) while in subpopulation AFR AF= 0.0267 (1110/41560). AF 95% confidence interval is 0.0254. There are 17 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 17 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3R5 | NM_001142633.3 | c.1885C>T | p.Pro629Ser | missense_variant | 12/19 | ENST00000447110.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3R5 | ENST00000447110.6 | c.1885C>T | p.Pro629Ser | missense_variant | 12/19 | 5 | NM_001142633.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00790 AC: 1203AN: 152190Hom.: 18 Cov.: 32
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GnomAD3 exomes AF: 0.00226 AC: 568AN: 250856Hom.: 7 AF XY: 0.00160 AC XY: 217AN XY: 135668
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GnomAD4 exome AF: 0.000859 AC: 1256AN: 1461730Hom.: 13 Cov.: 32 AF XY: 0.000719 AC XY: 523AN XY: 727164
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GnomAD4 genome ? AF: 0.00791 AC: 1205AN: 152308Hom.: 17 Cov.: 32 AF XY: 0.00771 AC XY: 574AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Ataxia with oculomotor apraxia type 3 Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2012 | - - |
Uncertain significance, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_001142633.2:c.1885C>T in the PIK3R5 gene has an allele frequency of 0.029 in African subpopulation in the gnomAD database. This variant has been detected in a consanguineous family with autosomal recessive ataxias, segregating with phenotypes (PMID: 22065524). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, PP1, PP4. - |
not specified Benign:2
Benign, criteria provided, single submitter | research | H3Africa Consortium | Oct 28, 2020 | While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.051, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2024 | Variant summary: PIK3R5 c.1885C>T (p.Pro629Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250856 control chromosomes, predominantly at a frequency of 0.029 within the African or African-American subpopulation in the gnomAD database, including 7 homozygotes, strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1885C>T has been reported in the literature in individuals affected with Ataxia With Oculomotor Apraxia, unspecified disease conditions and healthy donors (example, AlTassan_2012, Capalbo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia With Oculomotor Apraxia Type 3. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22065524, 31589614). ClinVar contains an entry for this variant (Variation ID: 48651). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
T;.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;.;T;.;T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;.
REVEL
Uncertain
Sift
Benign
T;.;.;.;.;.
Sift4G
Benign
T;T;T;T;T;T
Polyphen
P;.;.;.;P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at