Genetic Variant PIK3AP1:p.Thr726Lys (chr10-96604043-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152309.3(PIK3AP1):c.2177C>A(p.Thr726Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T726I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PIK3AP1
NM_152309.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.67

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057512045).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3AP1	NM_152309.3 link	c.2177C>A	p.Thr726Lys	missense_variant	Exon 15 of 17	ENST00000339364.10	NP_689522.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3AP1	ENST00000339364.10 link	c.2177C>A	p.Thr726Lys	missense_variant	Exon 15 of 17	1	NM_152309.3	ENSP00000339826.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447500

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719336

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33164

American (AMR)

AF:

0.0000229

AC:

AN:

43666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25830

East Asian (EAS)

AF:

0.00

AC:

AN:

39388

South Asian (SAS)

AF:

0.00

AC:

AN:

84108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1103130

Other (OTH)

AF:

0.00

AC:

AN:

59778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.15

T;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.058

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.;.

PhyloP100

1.7

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.52

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.47

T;T;T

Sift4G

Benign

0.71

T;T;T

Polyphen

0.066

B;.;B

Vest4

0.32

MutPred

0.26

Loss of phosphorylation at T726 (P = 0.0061);.;.;

MVP

0.14

MPC

0.69

ClinPred

0.053

GERP RS

3.1

Varity_R

0.020

gMVP

0.11

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over