Genetic Variant PIK3IP1:p.Val61Leu (chr22-31291186-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052880.5(PIK3IP1):c.181G>C(p.Val61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V61M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

PIK3IP1
NM_052880.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.391

Variant links:

Genes affected

PIK3IP1 (HGNC:24942): (phosphoinositide-3-kinase interacting protein 1) Enables phosphatidylinositol 3-kinase catalytic subunit binding activity. Involved in negative regulation of phosphatidylinositol 3-kinase activity and negative regulation of phosphatidylinositol 3-kinase signaling. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

PIK3IP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05324903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3IP1	NM_052880.5 link	c.181G>C	p.Val61Leu	missense_variant	Exon 2 of 6	ENST00000215912.10	NP_443112.2	Q96FE7-1A0A024R1M3
PIK3IP1	NM_001135911.1 link	c.181G>C	p.Val61Leu	missense_variant	Exon 2 of 5		NP_001129383.1	Q96FE7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIK3IP1	ENST00000215912.10 link	c.181G>C	p.Val61Leu	missense_variant	Exon 2 of 6	1	NM_052880.5	ENSP00000215912.4	Q96FE7-1
PIK3IP1	ENST00000402249.7 link	c.181G>C	p.Val61Leu	missense_variant	Exon 2 of 5	1		ENSP00000385204.3	Q96FE7-2
PIK3IP1	ENST00000441972.5 link	c.181G>C	p.Val61Leu	missense_variant	Exon 2 of 5	2		ENSP00000415608.1	Q96FE7-4
PIK3IP1	ENST00000443175.1 link	c.181G>C	p.Val61Leu	missense_variant	Exon 2 of 4	4		ENSP00000414227.1	C9JMK5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181G>C (p.V61L) alteration is located in exon 2 (coding exon 2) of the PIK3IP1 gene. This alteration results from a G to C substitution at nucleotide position 181, causing the valine (V) at amino acid position 61 to be replaced by a leucine (L). 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

0.080

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.9

DANN

Benign

0.56

DEOGEN2

Benign

0.0061

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.13

T;T;T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.053

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.11

N;N;N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.37

N;N;N;N

REVEL

Benign

0.048

Sift

Benign

0.66

T;T;T;T

Sift4G

Benign

0.52

T;T;T;.

Polyphen

0.0

B;.;B;.

Vest4

0.044

MutPred

0.39

Loss of catalytic residue at V61 (P = 0.1017);Loss of catalytic residue at V61 (P = 0.1017);Loss of catalytic residue at V61 (P = 0.1017);Loss of catalytic residue at V61 (P = 0.1017);

MVP

0.26

MPC

0.27

ClinPred

0.028

GERP RS

1.6

Varity_R

0.046

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over