Variant 18-62716014-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_194449.4(PHLPP1):c.331G>A(p.Gly111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,383,274 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 (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PHLPP1
NM_194449.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.848

Variant links:

Genes affected

PHLPP1 (HGNC:20610): (PH domain and leucine rich repeat protein phosphatase 1) This gene encodes a member of the serine/threonine phosphatase family. The encoded protein promotes apoptosis by dephosphorylating and inactivating the serine/threonine kinase Akt, and functions as a tumor suppressor in multiple types of cancer. Increased expression of this gene may also play a role in obesity and type 2 diabetes by interfering with Akt-mediated insulin signaling. [provided by RefSeq, Dec 2011]

PHLPP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12906009).

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHLPP1	NM_194449.4 linkuse as main transcript	c.331G>A	p.Gly111Arg	missense_variant	1/17	ENST00000262719.10	NP_919431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHLPP1	ENST00000262719.10 linkuse as main transcript	c.331G>A	p.Gly111Arg	missense_variant	1/17	1	NM_194449.4	ENSP00000262719	P1	O60346-1

Frequencies

GnomAD3 genomes

AF:

0.000173

AC:

AN:

150588

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000978

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000326

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000296

AC:

AN:

13502

Hom.:

AF XY:

0.000130

AC XY:

AN XY:

7716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000837

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000157

AC:

193

AN:

1232686

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

599520

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.000158

GnomAD4 genome

AF:

0.000173

AC:

AN:

150588

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

73506

show subpopulations

Gnomad4 AFR

AF:

0.0000486

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000978

Gnomad4 NFE

AF:

0.000326

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000216

Hom.:

Bravo

AF:

0.000117

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.331G>A (p.G111R) alteration is located in exon 1 (coding exon 1) of the PHLPP1 gene. This alteration results from a G to A substitution at nucleotide position 331, causing the glycine (G) at amino acid position 111 to be replaced by an arginine (R). 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

Uncertain

0.49

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.34

REVEL

Benign

0.031

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Vest4

0.15

MutPred

0.24

Gain of methylation at G111 (P = 0.0053);

MVP

0.043

MPC

1.8

ClinPred

0.27

GERP RS

2.9

Varity_R

0.057

gMVP

0.12

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