10-96645478-T-C

Position:

• chr10-96645478-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_152309.3(PIK3AP1):​c.1370A>G​(p.Asp457Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000633 in 1,612,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: PIK3AP1 NM_152309.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.13

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 10-96645478-T-C is Benign according to our data. Variant chr10-96645478-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541749.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3AP1	NM_152309.3	c.1370A>G	p.Asp457Gly	missense_variant	8/17	ENST00000339364.10	NP_689522.2
PIK3AP1	XM_011539248.2	c.1370A>G	p.Asp457Gly	missense_variant	8/16		XP_011537550.1
PIK3AP1	XM_005269499.2	c.836A>G	p.Asp279Gly	missense_variant	7/16		XP_005269556.1
PIK3AP1	XM_047424566.1	c.836A>G	p.Asp279Gly	missense_variant	9/18		XP_047280522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3AP1	ENST00000339364.10	c.1370A>G	p.Asp457Gly	missense_variant	8/17	1	NM_152309.3	ENSP00000339826.5
PIK3AP1	ENST00000371110.6	c.836A>G	p.Asp279Gly	missense_variant	7/16	2		ENSP00000360151.2
PIK3AP1	ENST00000468783.1	n.1016A>G		non_coding_transcript_exon_variant	7/8	5

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000372 AC: 93 AN: 250040 Hom.: 0 AF XY: 0.000377 AC XY: 51 AN XY: 135290

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000655 AC: 957 AN: 1460932 Hom.: 0 Cov.: 31 AF XY: 0.000665 AC XY: 483 AN XY: 726796

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000806

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.000431 AC XY: 32 AN XY: 74276

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000787

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000607 Hom.: 0

Bravo AF: 0.000404

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000436 AC: 53

EpiCase AF: 0.000709

EpiControl AF: 0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1370A>G (p.D457G) alteration is located in exon 8 (coding exon 8) of the PIK3AP1 gene. This alteration results from a A to G substitution at nucleotide position 1370, causing the aspartic acid (D) at amino acid position 457 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Infantile spasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;.
Vest4		0.85
MVP		0.35
MPC		1.4
ClinPred		0.46	T
GERP RS		5.8
Varity_R		0.40
gMVP		0.57

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: rs138047705; hg19: chr10-98405235;