rs146527410

Positions:

• chr10-96709780-C-A
• chr10-96709780-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_152309.3(PIK3AP1):​c.217G>T​(p.Ala73Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,613,502 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (10 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.73

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042536557).
• BP6: Variant 10-96709780-C-A is Benign according to our data. Variant chr10-96709780-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 474923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3AP1	NM_152309.3	c.217G>T	p.Ala73Ser	missense_variant	2/17	ENST00000339364.10	NP_689522.2
PIK3AP1	XM_011539248.2	c.217G>T	p.Ala73Ser	missense_variant	2/16		XP_011537550.1
PIK3AP1	XM_047424566.1	c.-318G>T		5_prime_UTR_variant	3/18		XP_047280522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.217G>T	p.Ala73Ser	missense_variant	2/17	1	NM_152309.3	ENSP00000339826.5

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 328 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00210 AC: 525 AN: 250574 Hom.: 3 AF XY: 0.00210 AC XY: 284 AN XY: 135542

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00538

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00278 AC: 4068 AN: 1461148 Hom.: 10 Cov.: 33 AF XY: 0.00273 AC XY: 1984 AN XY: 726742

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00345

Gnomad4 ASJ exome AF: 0.00701

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00201 AC XY: 150 AN XY: 74502

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00290

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00266 Hom.: 2

Bravo AF: 0.00252

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00261

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile spasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

PIK3AP1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.074
Sift	Benign	0.47	T
Sift4G	Benign	0.51	T
Polyphen		0.052	B
Vest4		0.17
MVP		0.42
MPC		0.51
ClinPred		0.0059	T
GERP RS		3.1
Varity_R		0.18
gMVP		0.33

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: rs146527410; hg19: chr10-98469537;