Genetic Variant PHLPP1:p.Ala135_Ala137del (chr18-62716074-TCCGCGGCCG-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_194449.4(PHLPP1):c.403_411delGCGGCCGCC(p.Ala135_Ala137del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,486,830 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00035 ( 2 hom. )

Consequence

PHLPP1
NM_194449.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_194449.4

BS2

High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHLPP1	NM_194449.4 link	c.403_411delGCGGCCGCC	p.Ala135_Ala137del	conservative_inframe_deletion	Exon 1 of 17	ENST00000262719.10	NP_919431.2	O60346-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHLPP1	ENST00000262719.10 link	c.403_411delGCGGCCGCC	p.Ala135_Ala137del	conservative_inframe_deletion	Exon 1 of 17	1	NM_194449.4	ENSP00000262719.4		O60346-1

Frequencies

GnomAD3 genomes

AF:

0.000416

AC:

AN:

148970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000520

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000624

Gnomad SAS

AF:

0.000430

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000507

Gnomad OTH

AF:

0.000486

GnomAD2 exomes

AF:

0.000588

AC:

AN:

86784

AF XY:

0.000496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000225

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000682

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000482

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000349

AC:

467

AN:

1337750

Hom.:

AF XY:

0.000386

AC XY:

254

AN XY:

658462

show subpopulations

African (AFR)

AF:

0.000332

AC:

AN:

27092

American (AMR)

AF:

0.000170

AC:

AN:

29356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22580

East Asian (EAS)

AF:

0.000279

AC:

AN:

32306

South Asian (SAS)

AF:

0.000823

AC:

AN:

72944

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32492

Middle Eastern (MID)

AF:

0.000465

AC:

AN:

4304

European-Non Finnish (NFE)

AF:

0.000343

AC:

364

AN:

1060938

Other (OTH)

AF:

0.000323

AC:

AN:

55738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000416

AC:

AN:

149080

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

AN XY:

72848

show subpopulations

African (AFR)

AF:

0.000519

AC:

AN:

40500

American (AMR)

AF:

0.0000661

AC:

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.000626

AC:

AN:

4794

South Asian (SAS)

AF:

0.000430

AC:

AN:

4650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.000507

AC:

AN:

67020

Other (OTH)

AF:

0.000482

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 30, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=263/37

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over