5-68226762-A-G

Position:

• chr5-68226762-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_181523.3(PIK3R1):​c.87A>G​(p.Ile29Met) 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 benign outcome for this variant. 14/21 in silico tools predict a benign 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: -1.42

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]

PIK3R1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3R1. . Gene score misZ 2.7206 (greater than the threshold 3.09). Trascript score misZ 3.4358 (greater than threshold 3.09). GenCC has associacion of gene with agammaglobulinemia 7, autosomal recessive, autosomal agammaglobulinemia, immunodeficiency 36, SHORT syndrome, activated PI3K-delta syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14557001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.87A>G	p.Ile29Met	missense_variant	2/16	ENST00000521381.6	NP_852664.1
PIK3R1	XM_005248542.4	c.87A>G	p.Ile29Met	missense_variant	2/16		XP_005248599.1
PIK3R1	XM_017009585.3	c.87A>G	p.Ile29Met	missense_variant	2/16		XP_016865074.1
PIK3R1	XM_047417315.1	c.87A>G	p.Ile29Met	missense_variant	2/16		XP_047273271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.87A>G	p.Ile29Met	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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.87A>G (p.I29M) alteration is located in exon 2 (coding exon 1) of the PIK3R1 gene. This alteration results from a A to G substitution at nucleotide position 87, causing the isoleucine (I) at amino acid position 29 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.1
DANN	Benign	0.89
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.12
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.0070	B;B
Vest4		0.38
MutPred		0.63		Loss of stability (P = 0.0948);Loss of stability (P = 0.0948);
MVP		0.36
MPC		0.14
ClinPred		0.12	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-67522590;