Variant 9-116154303-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002581.5(PAPPA):c.131C>G(p.Pro44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 926,362 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0025 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

PAPPA
NM_002581.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.967

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:

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=0.019928187).

BS2

High AC in GnomAd at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPPA	NM_002581.5 linkuse as main transcript	c.131C>G	p.Pro44Arg	missense_variant	1/22	ENST00000328252.4
PAPPA	XM_017014784.3 linkuse as main transcript	c.131C>G	p.Pro44Arg	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPPA	ENST00000328252.4 linkuse as main transcript	c.131C>G	p.Pro44Arg	missense_variant	1/22	1	NM_002581.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

359

AN:

145884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00864

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000408

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:

0.00

Gnomad OTH

AF:

0.000499

GnomAD4 exome

AF:

0.000176

AC:

137

AN:

780482

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

AN XY:

361766

show subpopulations

Gnomad4 AFR exome

AF:

0.00783

Gnomad4 AMR exome

AF:

0.00102

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000189

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000154

Gnomad4 OTH exome

AF:

0.000274

GnomAD4 genome

AF:

0.00245

AC:

358

AN:

145880

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

144

AN XY:

70902

show subpopulations

Gnomad4 AFR

AF:

0.00860

Gnomad4 AMR

AF:

0.000408

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000496

Alfa

AF:

0.000143

Hom.:

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

May 31, 2022

The c.131C>G (p.P44R) alteration is located in exon 1 (coding exon 1) of the PAPPA gene. This alteration results from a C to G substitution at nucleotide position 131, causing the proline (P) at amino acid position 44 to be replaced by an arginine (R). 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

Benign

0.091

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.26

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.30

M_CAP

Benign

0.018

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.53

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.82

REVEL

Benign

0.061

Sift

Benign

0.060

Sift4G

Uncertain

0.051

Polyphen

0.0060

Vest4

0.14

MutPred

0.28

Gain of methylation at P44 (P = 0.0042);

MVP

0.043

MPC

0.37

ClinPred

0.58

GERP RS

2.3

Varity_R

0.055

gMVP

0.45

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