NM_152309.3:c.2378C>T

Variant names:

• chr10-96595617-G-A
• rs140404891
• NM_152309.3:c.2378C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_152309.3(PIK3AP1):​c.2378C>T​(p.Thr793Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,004 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T793T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.274
• 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]

LOC105378443 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05251795).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3AP1	NM_152309.3	c.2378C>T	p.Thr793Ile	missense_variant	Exon 17 of 17	ENST00000339364.10	NP_689522.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.2378C>T	p.Thr793Ile	missense_variant	Exon 17 of 17	1	NM_152309.3	ENSP00000339826.5
PIK3AP1	ENST00000371109.3	c.1175C>T	p.Thr392Ile	missense_variant	Exon 10 of 10	1		ENSP00000360150.3
PIK3AP1	ENST00000371110.6	c.1844C>T	p.Thr615Ile	missense_variant	Exon 16 of 16	2		ENSP00000360151.2
PIK3AP1	ENST00000467625.5	n.575C>T		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248222 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461004 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 726744

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111696

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Infantile spasms Uncertain:1

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 793 of the PIK3AP1 protein (p.Thr793Ile). This variant is present in population databases (rs140404891, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with PIK3AP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1360489). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.43	T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;.;.
PhyloP100		0.27
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.076
MVP		0.082
MPC		0.58
ClinPred		0.071	T
GERP RS		0.13
Varity_R		0.017
gMVP		0.13
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: rs140404891; hg19: chr10-98355374;