rs12784975

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 24 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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152309.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3AP1	NM_152309.3	MANE Select	c.1913A>G	p.Lys638Arg	missense	Exon 12 of 17	NP_689522.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3AP1	ENST00000339364.10	TSL:1 MANE Select	c.1913A>G	p.Lys638Arg	missense	Exon 12 of 17	ENSP00000339826.5
	PIK3AP1	ENST00000371109.3	TSL:1	c.710A>G	p.Lys237Arg	missense	Exon 5 of 10	ENSP00000360150.3
	PIK3AP1	ENST00000371110.6	TSL:2	c.1379A>G	p.Lys460Arg	missense	Exon 11 of 16	ENSP00000360151.2

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

GnomAD2 exomes AF: 0.188 AC: 47224 AN: 251030 AF XY: 0.181

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 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

African (AFR) AF: 0.129 AC: 4327 AN: 33478

American (AMR) AF: 0.356 AC: 15943 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5696 AN: 26134

East Asian (EAS) AF: 0.0860 AC: 3416 AN: 39700

South Asian (SAS) AF: 0.109 AC: 9362 AN: 86258

European-Finnish (FIN) AF: 0.114 AC: 6080 AN: 53414

Middle Eastern (MID) AF: 0.249 AC: 1435 AN: 5764

European-Non Finnish (NFE) AF: 0.193 AC: 214543 AN: 1111888

Other (OTH) AF: 0.188 AC: 11359 AN: 60388

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

African (AFR) AF: 0.126 AC: 5242 AN: 41534

American (AMR) AF: 0.298 AC: 4555 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 723 AN: 3470

East Asian (EAS) AF: 0.106 AC: 549 AN: 5182

South Asian (SAS) AF: 0.0966 AC: 466 AN: 4822

European-Finnish (FIN) AF: 0.103 AC: 1088 AN: 10596

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13279 AN: 67982

Other (OTH) AF: 0.201 AC: 425 AN: 2110

Alfa AF: 0.186 Hom.: 9689

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Infantile spasms (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.89	L
PhyloP100		1.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.063
Sift	Benign	0.38	T
Sift4G	Benign	0.34	T
Polyphen		0.0030	B
Vest4		0.053
MPC		0.46
ClinPred		0.0044	T
GERP RS		3.6
Varity_R		0.065
gMVP		0.13
Mutation Taster		=96/4	polymorphism (auto)

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