Genetic Variant PHLPP1:p.Ala135_Ala137dup (chr18-62716074-T-TCCGCGGCCG) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_194449.4(PHLPP1):c.403_411dupGCGGCCGCC(p.Ala135_Ala137dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000135 in 1,486,724 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

PHLPP1
NM_194449.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_194449.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194449.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHLPP1	NM_194449.4	MANE Select	c.403_411dupGCGGCCGCC	p.Ala135_Ala137dup	conservative_inframe_insertion	Exon 1 of 17	NP_919431.2	O60346-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHLPP1	ENST00000262719.10	TSL:1 MANE Select	c.403_411dupGCGGCCGCC	p.Ala135_Ala137dup	conservative_inframe_insertion	Exon 1 of 17	ENSP00000262719.4	O60346-1
	PHLPP1	ENST00000937482.1		c.403_411dupGCGGCCGCC	p.Ala135_Ala137dup	conservative_inframe_insertion	Exon 1 of 16	ENSP00000607541.1

Frequencies

GnomAD3 genomes

AF:

0.00000671

AC:

AN:

148970

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:

0.000208

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.48e-7

AC:

AN:

1337754

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

658462

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27092

American (AMR)

AF:

0.00

AC:

AN:

29360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22580

East Asian (EAS)

AF:

0.0000310

AC:

AN:

32306

South Asian (SAS)

AF:

0.00

AC:

AN:

72942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1060940

Other (OTH)

AF:

0.00

AC:

AN:

55738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000671

AC:

AN:

148970

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72720

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

40382

American (AMR)

AF:

0.00

AC:

AN:

15102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.000208

AC:

AN:

4808

South Asian (SAS)

AF:

0.00

AC:

AN:

4654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67028

Other (OTH)

AF:

0.00

AC:

AN:

2058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=77/23

polymorphism

(source)

Splicing

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

Publications

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18-62716074-TCCGCGGCCG-TCCGCGGCCGCCGCGGCCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over