rs569632623

Variant names:

• chr10-96604034-C-T
• rs569632623
• NM_152309.3:c.2186G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_152309.3(PIK3AP1):​c.2186G>A​(p.Arg729His) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,604,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R729C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 5.02
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0097076595).
• BP6: Variant 10-96604034-C-T is Benign according to our data. Variant chr10-96604034-C-T is described in ClinVar as Benign. ClinVar VariationId is 474924.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 17 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3AP1	NM_152309.3	MANE Select	c.2186G>A	p.Arg729His	missense	Exon 15 of 17	NP_689522.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3AP1	ENST00000339364.10	TSL:1 MANE Select	c.2186G>A	p.Arg729His	missense	Exon 15 of 17	ENSP00000339826.5	Q6ZUJ8-1
	PIK3AP1	ENST00000371109.3	TSL:1	c.983G>A	p.Arg328His	missense	Exon 8 of 10	ENSP00000360150.3	Q6ZUJ8-3
	PIK3AP1	ENST00000866991.1		c.2186G>A	p.Arg729His	missense	Exon 15 of 17	ENSP00000537050.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000660 AC: 156 AN: 236420 AF XY: 0.000440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000865

GnomAD4 exome AF: 0.000126 AC: 183 AN: 1452268 Hom.: 0 Cov.: 30 AF XY: 0.000111 AC XY: 80 AN XY: 721706

African (AFR) AF: 0.00 AC: 0 AN: 33272

American (AMR) AF: 0.00398 AC: 175 AN: 43928

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25890

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39450

South Asian (SAS) AF: 0.00 AC: 0 AN: 84484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106724

Other (OTH) AF: 0.0000667 AC: 4 AN: 60008

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152256 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00111 AC: 17 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000438 Hom.: 0

Bravo AF: 0.000298

ExAC AF: 0.000569 AC: 69

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Infantile spasms (1)
-	-	1	PIK3AP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.53
MVP		0.40
MPC		1.7
ClinPred		0.094	T
GERP RS		5.2
Varity_R		0.33
gMVP		0.44
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs569632623; hg19: chr10-98363791; COSMIC: COSV59534166;