rs760805333

Positions:

chr10-96628436-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152309.3(PIK3AP1):c.1433G>A(p.Arg478Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,458 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PIK3AP1
NM_152309.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.205

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:

PIK3AP1 (HGNC:):

PIK3AP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019508809).

BS2

High AC in GnomAdExome4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3AP1	NM_152309.3 linkuse as main transcript	c.1433G>A	p.Arg478Gln	missense_variant	9/17	ENST00000339364.10	NP_689522.2	Q6ZUJ8-1Q86YV3
PIK3AP1	XM_011539248.2 linkuse as main transcript	c.1433G>A	p.Arg478Gln	missense_variant	9/16		XP_011537550.1
PIK3AP1	XM_005269499.2 linkuse as main transcript	c.899G>A	p.Arg300Gln	missense_variant	8/16		XP_005269556.1	Q6ZUJ8-2
PIK3AP1	XM_047424566.1 linkuse as main transcript	c.899G>A	p.Arg300Gln	missense_variant	10/18		XP_047280522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PIK3AP1	ENST00000339364.10 linkuse as main transcript	c.1433G>A	p.Arg478Gln	missense_variant	9/17	1	NM_152309.3	ENSP00000339826.5	Q6ZUJ8-1
PIK3AP1	ENST00000371109.3 linkuse as main transcript	c.230G>A	p.Arg77Gln	missense_variant	2/10	1		ENSP00000360150.3	Q6ZUJ8-3
PIK3AP1	ENST00000371110.6 linkuse as main transcript	c.899G>A	p.Arg300Gln	missense_variant	8/16	2		ENSP00000360151.2	Q6ZUJ8-2
PIK3AP1	ENST00000468783.1 linkuse as main transcript	n.1079G>A		non_coding_transcript_exon_variant	8/8	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251270

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461414

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000741

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2023

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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 574725). This variant has not been reported in the literature in individuals affected with PIK3AP1-related conditions. This variant is present in population databases (rs760805333, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 478 of the PIK3AP1 protein (p.Arg478Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.8

DANN

Benign

0.80

DEOGEN2

Benign

0.076

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.49

N;.;.

PrimateAI

Benign

0.19

PROVEAN

Benign

0.80

N;N;N

REVEL

Benign

0.015

Sift

Benign

0.59

T;T;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.026

B;.;B

Vest4

0.032

MutPred

0.32

Loss of MoRF binding (P = 0.0346);.;.;

MVP

0.21

MPC

0.62

ClinPred

0.011

GERP RS

-2.2

Varity_R

0.014

gMVP

0.15

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