5-68226700-A-G

Position:

• chr5-68226700-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_181523.3(PIK3R1):​c.25A>G​(p.Arg9Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0880

Genes affected

PIK3R1 (HGNC:8979): (phosphoinositide-3-kinase regulatory subunit 1) Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PIK3R1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 2.7206 (below the threshold of 3.09). Trascript score misZ: 3.4358 (above the threshold of 3.09). GenCC associations: The gene is linked to agammaglobulinemia 7, autosomal recessive, autosomal agammaglobulinemia, immunodeficiency 36, SHORT syndrome, activated PI3K-delta syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.25A>G	p.Arg9Gly	missense_variant	2/16	ENST00000521381.6	NP_852664.1
PIK3R1	XM_005248542.4	c.25A>G	p.Arg9Gly	missense_variant	2/16		XP_005248599.1
PIK3R1	XM_017009585.3	c.25A>G	p.Arg9Gly	missense_variant	2/16		XP_016865074.1
PIK3R1	XM_047417315.1	c.25A>G	p.Arg9Gly	missense_variant	2/16		XP_047273271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.25A>G	p.Arg9Gly	missense_variant	2/16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.55		Gain of catalytic residue at A10 (P = 0.0825);Gain of catalytic residue at A10 (P = 0.0825);
MVP		0.83
MPC		0.52
ClinPred		0.99	D
GERP RS		-4.2
Varity_R		0.90
gMVP		0.89

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: rs886043379; hg19: chr5-67522528;