Genetic Variant NM_001142633.3:c.2207G>T (chr17-8881880-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001142633.3(PIK3R5):c.2207G>T(p.Gly736Val) variant causes a missense, splice region 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. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PIK3R5
NM_001142633.3 missense, splice_region

Scores

Splicing: ADA: 0.001181

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

Publications

0 publications found

Variant links:

Genes affected

PIK3R5 (HGNC:30035): (phosphoinositide-3-kinase regulatory subunit 5) Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory subunit of the class I PI3K gamma complex, which is a dimeric enzyme, consisting of a 110 kD catalytic subunit gamma and a regulatory subunit of either 55, 87 or 101 kD. This protein recruits the catalytic subunit from the cytosol to the plasma membrane through high-affinity interaction with G-beta-gamma proteins. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found. [provided by RefSeq, Oct 2011]

PIK3R5 Gene-Disease associations (from GenCC):

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
ataxia with oculomotor apraxia type 3
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

PIK3R5 links:

LOC124903919 (HGNC:):

LOC124903919 links:

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ACMG classification

Classification was made for transcript

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=0.30443236).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142633.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R5	NM_001142633.3	MANE Select	c.2207G>T	p.Gly736Val	missense splice_region	Exon 16 of 19	NP_001136105.1	L7RT34
PIK3R5	NM_014308.4		c.2207G>T	p.Gly736Val	missense splice_region	Exon 16 of 19	NP_055123.2	Q8WYR1-1
PIK3R5	NM_001388396.1		c.2204G>T	p.Gly735Val	missense splice_region	Exon 16 of 19	NP_001375325.1	J3KSW1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R5	ENST00000447110.6	TSL:5 MANE Select	c.2207G>T	p.Gly736Val	missense splice_region	Exon 16 of 19	ENSP00000392812.1	Q8WYR1-1
PIK3R5	ENST00000581552.5	TSL:1	c.2207G>T	p.Gly736Val	missense splice_region	Exon 16 of 19	ENSP00000462433.1	Q8WYR1-1
PIK3R5	ENST00000623421.3	TSL:1	c.1049G>T	p.Gly350Val	missense splice_region	Exon 15 of 18	ENSP00000485280.1	Q8WYR1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726280

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

85964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110984

Other (OTH)

AF:

0.00

AC:

AN:

60338

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.14

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.010

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.83

M_CAP

Benign

0.034

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.2

PhyloP100

3.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.39

REVEL

Uncertain

0.34

Sift

Benign

0.35

Sift4G

Benign

0.46

Polyphen

0.029

Vest4

0.51

MutPred

0.64

Gain of sheet (P = 0.039)

MVP

0.72

MPC

0.61

ClinPred

0.48

GERP RS

4.6

PromoterAI

0.027

Neutral

(source)

Varity_R

0.16

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.028

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over