10-96602305-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.2335G>A(p.Val779Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,607,246 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V779L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.01

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]

LOC105378443 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07975295).
• BP6: Variant 10-96602305-C-T is Benign according to our data. Variant chr10-96602305-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 707691.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3AP1	NM_152309.3	c.2335G>A	p.Val779Met	missense_variant	16/17	ENST00000339364.10
LOC105378443	XR_946220.4	n.1447-5371C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.2335G>A	p.Val779Met	missense_variant	16/17	1	NM_152309.3	P1
PIK3AP1	ENST00000371109.3	c.1132G>A	p.Val378Met	missense_variant	9/10	1
PIK3AP1	ENST00000371110.6	c.1801G>A	p.Val601Met	missense_variant	15/16	2
PIK3AP1	ENST00000467625.5	n.532G>A		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000393 AC: 96 AN: 244474 Hom.: 1 AF XY: 0.000408 AC XY: 54 AN XY: 132394

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.000615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000342

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.000681

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000355 AC: 516 AN: 1455002 Hom.: 1 Cov.: 30 AF XY: 0.000344 AC XY: 249 AN XY: 723952

Gnomad4 AFR exome AF: 0.0000910

Gnomad4 AMR exome AF: 0.0000235

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000769

Gnomad4 NFE exome AF: 0.000393

Gnomad4 OTH exome AF: 0.000383

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74452

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.000273

EpiControl AF: 0.000594

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

Oct 12, 2022

The c.2335G>A (p.V779M) alteration is located in exon 16 (coding exon 16) of the PIK3AP1 gene. This alteration results from a G to A substitution at nucleotide position 2335, causing the valine (V) at amino acid position 779 to be replaced by a methionine (M). 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

Invitae

Oct 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.75	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.92	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.94	P;.;D
Vest4		0.34
MVP		0.40
MPC		1.4
ClinPred		0.066	T
GERP RS		3.0
Varity_R		0.053
gMVP		0.22

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: rs45587542; hg19: chr10-98362062;