rs12784975

Variant names:

• chr10-96620380-T-C
• rs12784975
• NM_152309.3:c.1913A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152309.3(PIK3AP1):​c.1913A>G​(p.Lys638Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,613,944 control chromosomes in the GnomAD database, including 29,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2612 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27060 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.70

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011126697).
• BP6: Variant 10-96620380-T-C is Benign according to our data. Variant chr10-96620380-T-C is described in ClinVar as [Benign]. Clinvar id is 1169953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3AP1	NM_152309.3	c.1913A>G	p.Lys638Arg	missense_variant	Exon 12 of 17	ENST00000339364.10	NP_689522.2
PIK3AP1	XM_011539248.2	c.1913A>G	p.Lys638Arg	missense_variant	Exon 12 of 16		XP_011537550.1
PIK3AP1	XM_005269499.2	c.1379A>G	p.Lys460Arg	missense_variant	Exon 11 of 16		XP_005269556.1
PIK3AP1	XM_047424566.1	c.1379A>G	p.Lys460Arg	missense_variant	Exon 13 of 18		XP_047280522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.1913A>G	p.Lys638Arg	missense_variant	Exon 12 of 17	1	NM_152309.3	ENSP00000339826.5
PIK3AP1	ENST00000371109.3	c.710A>G	p.Lys237Arg	missense_variant	Exon 5 of 10	1		ENSP00000360150.3
PIK3AP1	ENST00000371110.6	c.1379A>G	p.Lys460Arg	missense_variant	Exon 11 of 16	2		ENSP00000360151.2
PIK3AP1	ENST00000489982.1	n.32A>G		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26461 AN: 152078 Hom.: 2611 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.203

GnomAD3 exomes AF: 0.188 AC: 47224 AN: 251030 Hom.: 5355 AF XY: 0.181 AC XY: 24594 AN XY: 135724

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.186 AC: 272161 AN: 1461748 Hom.: 27060 Cov.: 34 AF XY: 0.184 AC XY: 133448 AN XY: 727174

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.356

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.0860

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.193

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.174 AC: 26469 AN: 152196 Hom.: 2612 Cov.: 32 AF XY: 0.168 AC XY: 12533 AN XY: 74402

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.0966

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.201

Alfa AF: 0.190 Hom.: 4675

Bravo AF: 0.190

TwinsUK AF: 0.201 AC: 744

ALSPAC AF: 0.188 AC: 723

ESP6500AA AF: 0.123 AC: 542

ESP6500EA AF: 0.195 AC: 1676

ExAC AF: 0.178 AC: 21675

Asia WGS AF: 0.106 AC: 369 AN: 3478

EpiCase AF: 0.201

EpiControl AF: 0.205

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile spasms Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0011	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.89	L;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.45	N;N;N
REVEL	Benign	0.063
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.053
MPC		0.46
ClinPred		0.0044	T
GERP RS		3.6
Varity_R		0.065
gMVP		0.13

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: rs12784975; hg19: chr10-98380137; COSMIC: COSV59535559; COSMIC: COSV59535559;