Genetic Variant NM_002581.5:c.131C>G (chr9-116154303-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P44Q) has been classified 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

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019928187).

BS2

High AC in GnomAd4 at 358 AD gene.

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.131C>G	p.Pro44Arg	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.131C>G	p.Pro44Arg	missense	Exon 1 of 22	ENSP00000330658.3	Q13219
ENSG00000298241	ENST00000754065.1		n.229+448G>C		intron	N/A
ENSG00000298241	ENST00000754066.1		n.398+448G>C		intron	N/A

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

African (AFR)

AF:

0.00783

AC:

115

AN:

14684

American (AMR)

AF:

0.00102

AC:

AN:

982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4846

East Asian (EAS)

AF:

0.00

AC:

AN:

3388

South Asian (SAS)

AF:

0.000189

AC:

AN:

15912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1526

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

713230

Other (OTH)

AF:

0.000274

AC:

AN:

25534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.00245

AC:

358

AN:

145880

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

144

AN XY:

70902

show subpopulations

African (AFR)

AF:

0.00860

AC:

351

AN:

40794

American (AMR)

AF:

0.000408

AC:

AN:

14722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.00

AC:

AN:

4968

South Asian (SAS)

AF:

0.00

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65744

Other (OTH)

AF:

0.000496

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000143

Hom.:

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

0.091

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

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

PhyloP100

0.97

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

Mutation Taster

=97/3

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over