Genetic Variant PAPPA:p.Glu70Gly (chr9-116154381-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002581.5(PAPPA):c.209A>G(p.Glu70Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PAPPA
NM_002581.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

Publications

0 publications found

Variant links:

Genes affected

PAPPA (HGNC:8602): (pappalysin 1) This gene encodes a secreted metalloproteinase which cleaves insulin-like growth factor binding proteins (IGFBPs). Following IGFBP cleavage, insulin growth factors dissociate from IGFBPs and bind to IGF receptors, resulting in activation of the IGF pathway. The encoded protein plays a role in bone formation, inflammation, wound healing and female fertility. Enhanced expression of this protein is associated with diabetic nephropathy in human patients and this protein may promote tumor invasion and growth in various human cancers. [provided by RefSeq, Aug 2017]

PAPPA links:

ENSG00000298241 (HGNC:):

ENSG00000298241 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0795348).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002581.5. 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
	PAPPA	NM_002581.5	MANE Select	c.209A>G	p.Glu70Gly	missense	Exon 1 of 22	NP_002572.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAPPA	ENST00000328252.4	TSL:1 MANE Select	c.209A>G	p.Glu70Gly	missense	Exon 1 of 22	ENSP00000330658.3	Q13219
ENSG00000298241	ENST00000754065.1		n.229+370T>C		intron	N/A
ENSG00000298241	ENST00000754066.1		n.398+370T>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

910956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

436724

African (AFR)

AF:

0.00

AC:

AN:

18502

American (AMR)

AF:

0.00

AC:

AN:

7208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11884

East Asian (EAS)

AF:

0.00

AC:

AN:

22910

South Asian (SAS)

AF:

0.00

AC:

AN:

20772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2482

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

771684

Other (OTH)

AF:

0.00

AC:

AN:

36150

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.39

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.080

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.0

PhyloP100

1.4

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.42

REVEL

Benign

0.034

Sift

Uncertain

0.012

Sift4G

Benign

0.18

Polyphen

0.0020

Vest4

0.037

MutPred

0.23

Gain of loop (P = 0.0195)

MVP

0.043

MPC

0.42

ClinPred

0.30

GERP RS

2.5

Varity_R

0.12

gMVP

0.58

Mutation Taster

=77/23

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over