chr1-46043867-C-G

Variant names:

• chr1-46043867-C-G
• rs755888231
• NM_003629.4:c.1192G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003629.4. 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
	PIK3R3	NM_003629.4	MANE Select	c.1192G>C	p.Asp398His	missense	Exon 10 of 10	NP_003620.3
	P3R3URF-PIK3R3	NM_001303427.2		c.1330G>C	p.Asp444His	missense	Exon 10 of 10	NP_001290356.1	F6TDL0
	PIK3R3	NM_001303428.1		c.1243G>C	p.Asp415His	missense	Exon 11 of 11	NP_001290357.1	B4DXM8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R3	ENST00000262741.10	TSL:1 MANE Select	c.1192G>C	p.Asp398His	missense	Exon 10 of 10	ENSP00000262741.5	Q92569-1
	P3R3URF-PIK3R3	ENST00000540385.2	TSL:2	c.1330G>C	p.Asp444His	missense	Exon 10 of 10	ENSP00000439913.1	F6TDL0
	PIK3R3	ENST00000372006.5	TSL:1	c.1192G>C	p.Asp398His	missense	Exon 11 of 11	ENSP00000361075.1	Q92569-1

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

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111148

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.53	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.97	D
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
Mutation Taster		=48/52	disease causing

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: rs755888231; hg19: chr1-46509539;