10-96623472-C-T

Variant names:

• chr10-96623472-C-T
• rs144966728
• NM_152309.3:c.1735G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The NM_152309.3(PIK3AP1):​c.1735G>A​(p.Gly579Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000378 in 1,609,772 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G579W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense, splice_region
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.15
• Publications: 3 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 -11 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 10-96623472-C-T is Benign according to our data. Variant chr10-96623472-C-T is described in ClinVar as Benign. ClinVar VariationId is 541757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 68 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.1735G>A	p.Gly579Arg	missense splice_region	Exon 11 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.1735G>A	p.Gly579Arg	missense splice_region	Exon 11 of 17	ENSP00000339826.5	Q6ZUJ8-1
	PIK3AP1	ENST00000371109.3	TSL:1	c.532G>A	p.Gly178Arg	missense splice_region	Exon 4 of 10	ENSP00000360150.3	Q6ZUJ8-3
	PIK3AP1	ENST00000866991.1		c.1735G>A	p.Gly579Arg	missense splice_region	Exon 11 of 17	ENSP00000537050.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000709 AC: 178 AN: 251216 AF XY: 0.000714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000370 AC: 540 AN: 1457616 Hom.: 2 Cov.: 30 AF XY: 0.000374 AC XY: 271 AN XY: 725356

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 393 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

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

European-Non Finnish (NFE) AF: 0.0000532 AC: 59 AN: 1108470

Other (OTH) AF: 0.00144 AC: 87 AN: 60262

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68030

Other (OTH) AF: 0.000960 AC: 2 AN: 2084

Alfa AF: 0.000777 Hom.: 1

Bravo AF: 0.000431

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000576 AC: 70

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

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	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.11
Sift	Benign	0.053	T
Sift4G	Benign	0.073	T
Polyphen		0.28	B
Vest4		0.14
MutPred		0.18		Gain of MoRF binding (P = 0.0123)
MVP		0.19
MPC		0.66
ClinPred		0.046	T
GERP RS		5.6
Varity_R		0.095
gMVP		0.28
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.030		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: rs144966728; hg19: chr10-98383229;