10-96595617-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152309.3(PIK3AP1):c.2378C>T(p.Thr793Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T793T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PIK3AP1
NM_152309.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.274

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]

PIK3AP1 links:

LOC105378443 (HGNC:):

LOC105378443 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05251795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3AP1	NM_152309.3 linkuse as main transcript	c.2378C>T	p.Thr793Ile	missense_variant	17/17	ENST00000339364.10
LOC105378443	XR_946220.4 linkuse as main transcript	n.1446+4033G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3AP1	ENST00000339364.10 linkuse as main transcript	c.2378C>T	p.Thr793Ile	missense_variant	17/17	1	NM_152309.3	P1	Q6ZUJ8-1
PIK3AP1	ENST00000371109.3 linkuse as main transcript	c.1175C>T	p.Thr392Ile	missense_variant	10/10	1			Q6ZUJ8-3
PIK3AP1	ENST00000371110.6 linkuse as main transcript	c.1844C>T	p.Thr615Ile	missense_variant	16/16	2			Q6ZUJ8-2
PIK3AP1	ENST00000467625.5 linkuse as main transcript	n.575C>T		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

248222

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461004

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726744

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

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 submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 793 of the PIK3AP1 protein (p.Thr793Ile). This variant is present in population databases (rs140404891, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with PIK3AP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1360489). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.43

T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.26

N;N;N

REVEL

Benign

0.050

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.47

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.076

MVP

0.082

MPC

0.58

ClinPred

0.071

GERP RS

0.13

Varity_R

0.017

gMVP

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over