10-96602286-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152309.3(PIK3AP1):c.2354C>T(p.Ser785Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,451,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

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=0.22935122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3AP1	NM_152309.3	c.2354C>T	p.Ser785Leu	missense_variant	16/17	ENST00000339364.10
LOC105378443	XR_946220.4	n.1447-5390G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.2354C>T	p.Ser785Leu	missense_variant	16/17	1	NM_152309.3	P1
PIK3AP1	ENST00000371109.3	c.1151C>T	p.Ser384Leu	missense_variant	9/10	1
PIK3AP1	ENST00000371110.6	c.1820C>T	p.Ser607Leu	missense_variant	15/16	2
PIK3AP1	ENST00000467625.5	n.551C>T		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000819 AC: 2 AN: 244324 Hom.: 0 AF XY: 0.00000756 AC XY: 1 AN XY: 132298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000620

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: 0.00000138 AC: 2 AN: 1451170 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000471

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

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

Sep 08, 2021

This sequence change replaces serine with leucine at codon 785 of the PIK3AP1 protein (p.Ser785Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs769596130, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with PIK3AP1-related conditions. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.57	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.29
MutPred		0.21		Loss of phosphorylation at S785 (P = 0.0017);.;.;
MVP		0.41
MPC		1.4
ClinPred		0.64	D
GERP RS		4.2
Varity_R		0.072
gMVP		0.18

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: rs769596130; hg19: chr10-98362043;