Genetic Variant PPP5C:p.Met1? (chr19-46347098-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_006247.4(PPP5C):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PPP5C
NM_006247.4 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04

Publications

1 publications found

Variant links:

Genes affected

PPP5C (HGNC:9322): (protein phosphatase 5 catalytic subunit) This gene encodes a serine/threonine phosphatase which is a member of the protein phosphatase catalytic subunit family. Proteins in this family participate in pathways regulated by reversible phosphorylation at serine and threonine residues; many of these pathways are involved in the regulation of cell growth and differentiation. The product of this gene has been shown to participate in signaling pathways in response to hormones or cellular stress, and elevated levels of this protein may be associated with breast cancer development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

PPP5C links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 codons. Genomic position: 46347103. Lost 0.005 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006247.4. 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
	PPP5C	NM_006247.4	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 13	NP_006238.1	P53041
	PPP5C	NM_001204284.2		c.2T>A	p.Met1?	start_lost	Exon 1 of 12	NP_001191213.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP5C	ENST00000012443.9	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 13	ENSP00000012443.4	P53041
PPP5C	ENST00000923870.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 13	ENSP00000593929.1
PPP5C	ENST00000886857.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 13	ENSP00000556916.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33176

American (AMR)

AF:

0.00

AC:

AN:

42924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25818

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39074

South Asian (SAS)

AF:

0.00

AC:

AN:

84348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106222

Other (OTH)

AF:

0.00

AC:

AN:

59768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.25

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-1.0

PhyloP100

1.0

PROVEAN

Benign

-0.29

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.016

Polyphen

0.0010

Vest4

0.65

MutPred

0.98

Gain of ubiquitination at M1 (P = 0.0114)

MVP

0.61

ClinPred

1.0

GERP RS

3.2

PromoterAI

-0.32

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.95

gMVP

0.69

Mutation Taster

=176/24

polymorphism

(source)

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

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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