NM_001142633.3:c.1885C>T
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
Consequence
NM_001142633.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00790 AC: 1203AN: 152190Hom.: 18 Cov.: 32
GnomAD3 exomes AF: 0.00226 AC: 568AN: 250856Hom.: 7 AF XY: 0.00160 AC XY: 217AN XY: 135668
GnomAD4 exome AF: 0.000859 AC: 1256AN: 1461730Hom.: 13 Cov.: 32 AF XY: 0.000719 AC XY: 523AN XY: 727164
GnomAD4 genome AF: 0.00791 AC: 1205AN: 152308Hom.: 17 Cov.: 32 AF XY: 0.00771 AC XY: 574AN XY: 74480
ClinVar
Submissions by phenotype
Ataxia with oculomotor apraxia type 3 Pathogenic:1Uncertain:2
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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
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. -
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at