1-46043867-C-G

Position:

• chr1-46043867-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003629.4(PIK3R3):​c.1192G>C​(p.Asp398His) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,378 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D398N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIK3R3 NM_003629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

Genes affected

PIK3R3 (HGNC:8981): (phosphoinositide-3-kinase regulatory subunit 3) Phosphatidylinositol 3-kinase (PI3K) phosphorylates phosphatidylinositol and similar compounds, which then serve as second messengers in growth signaling pathways. PI3K is composed of a catalytic and a regulatory subunit. The protein encoded by this gene represents a regulatory subunit of PI3K. The encoded protein contains two SH2 domains through which it binds activated protein tyrosine kinases to regulate their activity. [provided by RefSeq, Jun 2016]

P3R3URF-PIK3R3 (HGNC:54999): (P3R3URF-PIK3R3 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring genes LOC110117498 and PIK3R3. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

PIK3R3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41004068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R3	NM_003629.4	c.1192G>C	p.Asp398His	missense_variant	10/10	ENST00000262741.10	NP_003620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R3	ENST00000262741.10	c.1192G>C	p.Asp398His	missense_variant	10/10	1	NM_003629.4	ENSP00000262741.5
P3R3URF-PIK3R3	ENST00000540385.2	c.1330G>C	p.Asp444His	missense_variant	10/10	2		ENSP00000439913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460378 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2024

The c.1192G>C (p.D398H) alteration is located in exon 10 (coding exon 10) of the PIK3R3 gene. This alteration results from a G to C substitution at nucleotide position 1192, causing the aspartic acid (D) at amino acid position 398 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;D;D;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.53	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.6	L;L;L;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.97	D;D;D;P;.
Vest4		0.34
MutPred		0.68		.;.;.;.;Gain of loop (P = 0.0045);
MVP		0.97
MPC		0.56
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.56

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: rs755888231; hg19: chr1-46509539;