Variant 10-96656811-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152309.3(PIK3AP1):c.554G>A(p.Arg185His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,726 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: 0.0000062 ( 0 hom. )

Consequence

PIK3AP1
NM_152309.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.37

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1891118).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3AP1	NM_152309.3 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	3/17	ENST00000339364.10	NP_689522.2	Q6ZUJ8-1Q86YV3
PIK3AP1	XM_011539248.2 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	3/16		XP_011537550.1
PIK3AP1	XM_005269499.2 linkuse as main transcript	c.20G>A	p.Arg7His	missense_variant	2/16		XP_005269556.1	Q6ZUJ8-2
PIK3AP1	XM_047424566.1 linkuse as main transcript	c.20G>A	p.Arg7His	missense_variant	4/18		XP_047280522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PIK3AP1	ENST00000339364.10 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	3/17	1	NM_152309.3	ENSP00000339826.5	Q6ZUJ8-1
PIK3AP1	ENST00000371110.6 linkuse as main transcript	c.20G>A	p.Arg7His	missense_variant	2/16	2		ENSP00000360151.2	Q6ZUJ8-2
PIK3AP1	ENST00000468783.1 linkuse as main transcript	n.200G>A		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

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

Aug 09, 2022

This variant is present in population databases (no rsID available, gnomAD 0.03%). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 541751). This variant has not been reported in the literature in individuals affected with PIK3AP1-related conditions. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 185 of the PIK3AP1 protein (p.Arg185His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

0.0060

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.0046

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.035

Sift

Benign

0.082

T;T

Sift4G

Uncertain

0.059

T;T

Polyphen

0.22

B;.

Vest4

0.35

MutPred

0.45

Loss of solvent accessibility (P = 0.0299);.;

MVP

0.15

MPC

1.0

ClinPred

0.77

GERP RS

5.1

Varity_R

0.24

gMVP

0.65

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