Variant 18-62715760-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_194449.4(PHLPP1):c.77C>A(p.Ala26Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,096,308 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

PHLPP1
NM_194449.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.182

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043279707).

BS2

High AC in GnomAd4 at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHLPP1	NM_194449.4 linkuse as main transcript	c.77C>A	p.Ala26Asp	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.77C>A	p.Ala26Asp	missense_variant	1/17	1	NM_194449.4	ENSP00000262719	P1	O60346-1

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

193

AN:

147594

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00436

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000805

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:

0.0000302

Gnomad OTH

AF:

0.000493

GnomAD4 exome

AF:

0.000106

AC:

101

AN:

948612

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

446340

show subpopulations

Gnomad4 AFR exome

AF:

0.00416

Gnomad4 AMR exome

AF:

0.000552

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:

0.00

Gnomad4 OTH exome

AF:

0.000474

GnomAD4 genome

AF:

0.00131

AC:

193

AN:

147696

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

71972

show subpopulations

Gnomad4 AFR

AF:

0.00437

Gnomad4 AMR

AF:

0.000737

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000302

Gnomad4 OTH

AF:

0.000488

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.00179

ExAC

AF:

0.000118

AC:

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

Aug 02, 2022

The c.77C>A (p.A26D) alteration is located in exon 1 (coding exon 1) of the PHLPP1 gene. This alteration results from a C to A substitution at nucleotide position 77, causing the alanine (A) at amino acid position 26 to be replaced by an aspartic acid (D). 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

0.35

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.059

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.33

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

D;N

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.090

REVEL

Benign

0.039

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.031

Vest4

0.29

MutPred

0.28

Loss of helix (P = 0.0068);

MVP

0.13

MPC

2.1

ClinPred

0.38

GERP RS

2.0

Varity_R

0.32

gMVP

0.50

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