rs3748233

Positions:

• chr10-96626726-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152309.3(PIK3AP1):​c.1651G>A​(p.Glu551Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,614,126 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (55 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.27

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006027162).
• BP6: Variant 10-96626726-C-T is Benign according to our data. Variant chr10-96626726-C-T is described in ClinVar as [Benign]. Clinvar id is 474917.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00112 (170/152324) while in subpopulation EAS AF= 0.0237 (123/5180). AF 95% confidence interval is 0.0203. There are 2 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 170 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3AP1	NM_152309.3	c.1651G>A	p.Glu551Lys	missense_variant	10/17	ENST00000339364.10	NP_689522.2
PIK3AP1	XM_011539248.2	c.1651G>A	p.Glu551Lys	missense_variant	10/16		XP_011537550.1
PIK3AP1	XM_005269499.2	c.1117G>A	p.Glu373Lys	missense_variant	9/16		XP_005269556.1
PIK3AP1	XM_047424566.1	c.1117G>A	p.Glu373Lys	missense_variant	11/18		XP_047280522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.1651G>A	p.Glu551Lys	missense_variant	10/17	1	NM_152309.3	ENSP00000339826	P1
PIK3AP1	ENST00000371109.3	c.448G>A	p.Glu150Lys	missense_variant	3/10	1		ENSP00000360150
PIK3AP1	ENST00000371110.6	c.1117G>A	p.Glu373Lys	missense_variant	9/16	2		ENSP00000360151

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152206 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00196 AC: 491 AN: 251100 Hom.: 7 AF XY: 0.00202 AC XY: 274 AN XY: 135712

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0164

Gnomad SAS exome AF: 0.00555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00148 AC: 2159 AN: 1461802 Hom.: 55 Cov.: 56 AF XY: 0.00158 AC XY: 1148 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0404

Gnomad4 SAS exome AF: 0.00490

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152324 Hom.: 2 Cov.: 34 AF XY: 0.00141 AC XY: 105 AN XY: 74490

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0237

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000534 Hom.: 0

Bravo AF: 0.000835

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Infantile spasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	0.093
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0060	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.45	N;N;N
REVEL	Benign	0.074
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.60	P;.;P
Vest4		0.42
MVP		0.32
MPC		0.62
ClinPred		0.016	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.14
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3748233; hg19: chr10-98386483; COSMIC: COSV59531041; COSMIC: COSV59531041;