chr10-96595608-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152309.3(PIK3AP1):​c.2387C>A​(p.Pro796His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PIK3AP1
NM_152309.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08
Variant links:
Genes affected
PIK3AP1 (HGNC:30034): (phosphoinositide-3-kinase adaptor protein 1) Predicted to enable phosphatidylinositol 3-kinase regulatory subunit binding activity and signaling receptor binding activity. Predicted to be involved in regulation of inflammatory response; regulation of signal transduction; and toll-like receptor signaling pathway. Predicted to be located in cytoplasm and membrane. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.091227055).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PIK3AP1NM_152309.3 linkuse as main transcriptc.2387C>A p.Pro796His missense_variant 17/17 ENST00000339364.10 NP_689522.2
LOC105378443XR_946220.4 linkuse as main transcriptn.1446+4024G>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PIK3AP1ENST00000339364.10 linkuse as main transcriptc.2387C>A p.Pro796His missense_variant 17/171 NM_152309.3 ENSP00000339826 P1Q6ZUJ8-1
PIK3AP1ENST00000371109.3 linkuse as main transcriptc.1184C>A p.Pro395His missense_variant 10/101 ENSP00000360150 Q6ZUJ8-3
PIK3AP1ENST00000371110.6 linkuse as main transcriptc.1853C>A p.Pro618His missense_variant 16/162 ENSP00000360151 Q6ZUJ8-2
PIK3AP1ENST00000467625.5 linkuse as main transcriptn.584C>A non_coding_transcript_exon_variant 6/63

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
248446
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
134020
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461070
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
726776
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Infantile spasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PIK3AP1-related conditions. This variant is present in population databases (rs746172807, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 796 of the PIK3AP1 protein (p.Pro796His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T;.;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.10
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.65
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.091
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;.;.
MutationTaster
Benign
0.57
D;D;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.67
N;N;N
REVEL
Benign
0.039
Sift
Uncertain
0.013
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
0.0030
B;.;B
Vest4
0.26
MutPred
0.20
Loss of glycosylation at P796 (P = 0.0065);.;.;
MVP
0.17
MPC
1.5
ClinPred
0.39
T
GERP RS
3.7
Varity_R
0.054
gMVP
0.12

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

LitVar

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

Other links and lift over

dbSNP: rs746172807; hg19: chr10-98355365; API