10-96595608-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P796R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08

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]

LOC105378443 (HGNC:):

ACMG classification

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	UniProt
PIK3AP1	NM_152309.3	c.2387C>A	p.Pro796His	missense_variant	17/17	ENST00000339364.10
LOC105378443	XR_946220.4	n.1446+4024G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.2387C>A	p.Pro796His	missense_variant	17/17	1	NM_152309.3	P1
PIK3AP1	ENST00000371109.3	c.1184C>A	p.Pro395His	missense_variant	10/10	1
PIK3AP1	ENST00000371110.6	c.1853C>A	p.Pro618His	missense_variant	16/16	2
PIK3AP1	ENST00000467625.5	n.584C>A		non_coding_transcript_exon_variant	6/6	3

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

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

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

Submissions by phenotype

Infantile spasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2022

In 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

Other links and lift over

dbSNP: rs746172807; hg19: chr10-98355365;