10-96626713-A-T

Variant names:

• chr10-96626713-A-T
• rs781326320
• NM_152309.3:c.1664T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152309.3(PIK3AP1):​c.1664T>A​(p.Phe555Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. F555S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102185816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3AP1	NM_152309.3	c.1664T>A	p.Phe555Tyr	missense_variant	Exon 10 of 17	ENST00000339364.10	NP_689522.2
PIK3AP1	XM_011539248.2	c.1664T>A	p.Phe555Tyr	missense_variant	Exon 10 of 16		XP_011537550.1
PIK3AP1	XM_005269499.2	c.1130T>A	p.Phe377Tyr	missense_variant	Exon 9 of 16		XP_005269556.1
PIK3AP1	XM_047424566.1	c.1130T>A	p.Phe377Tyr	missense_variant	Exon 11 of 18		XP_047280522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.1664T>A	p.Phe555Tyr	missense_variant	Exon 10 of 17	1	NM_152309.3	ENSP00000339826.5
PIK3AP1	ENST00000371109.3	c.461T>A	p.Phe154Tyr	missense_variant	Exon 3 of 10	1		ENSP00000360150.3
PIK3AP1	ENST00000371110.6	c.1130T>A	p.Phe377Tyr	missense_variant	Exon 9 of 16	2		ENSP00000360151.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461530 Hom.: 0 Cov.: 55 AF XY: 0.00000138 AC XY: 1 AN XY: 727010

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111724

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.077	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	N;.;.
PhyloP100		3.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.020	N;N;N
REVEL	Benign	0.091
Sift	Benign	0.26	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.077	B;.;B
Vest4		0.26
MutPred		0.56		Gain of phosphorylation at F555 (P = 0.0226);.;.;
MVP		0.19
MPC		0.61
ClinPred		0.62	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.35
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs781326320; hg19: chr10-98386470;