rs201358424

Positions:

• chr10-96620549-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_152309.3(PIK3AP1):​c.1744G>A​(p.Val582Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000571 in 1,612,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.11

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

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08286765).
• BP6: Variant 10-96620549-C-T is Benign according to our data. Variant chr10-96620549-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541745.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3AP1	NM_152309.3	c.1744G>A	p.Val582Ile	missense_variant	12/17	ENST00000339364.10	NP_689522.2
PIK3AP1	XM_011539248.2	c.1744G>A	p.Val582Ile	missense_variant	12/16		XP_011537550.1
PIK3AP1	XM_005269499.2	c.1210G>A	p.Val404Ile	missense_variant	11/16		XP_005269556.1
PIK3AP1	XM_047424566.1	c.1210G>A	p.Val404Ile	missense_variant	13/18		XP_047280522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.1744G>A	p.Val582Ile	missense_variant	12/17	1	NM_152309.3	ENSP00000339826	P1
PIK3AP1	ENST00000371109.3	c.541G>A	p.Val181Ile	missense_variant	5/10	1		ENSP00000360150
PIK3AP1	ENST00000371110.6	c.1210G>A	p.Val404Ile	missense_variant	11/16	2		ENSP00000360151

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000100 AC: 25 AN: 249318 Hom.: 0 AF XY: 0.0000963 AC XY: 13 AN XY: 134928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000981

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000562 AC: 82 AN: 1460168 Hom.: 0 Cov.: 37 AF XY: 0.0000496 AC XY: 36 AN XY: 726330

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74432

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000860 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.1744G>A (p.V582I) alteration is located in exon 12 (coding exon 12) of the PIK3AP1 gene. This alteration results from a G to A substitution at nucleotide position 1744, causing the valine (V) at amino acid position 582 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Infantile spasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.60	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.064	T;T;D
Sift4G	Benign	0.13	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.21
MVP		0.41
MPC		0.60
ClinPred		0.15	T
GERP RS		4.6
Varity_R		0.080
gMVP		0.23

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

Other links and lift over

dbSNP: rs201358424; hg19: chr10-98380306;