Genetic Variant NM_002581.5:c.265G>C (chr9-116154437-G-C) – 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.265G>C(p.Glu89Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,274,326 control chromosomes in the GnomAD database, including 1 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

PAPPA
NM_002581.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0670031).

BS2

High AC in GnomAdExome4 at 18 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.265G>C	p.Glu89Gln	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.265G>C	p.Glu89Gln	missense	Exon 1 of 22	ENSP00000330658.3	Q13219
ENSG00000298241	ENST00000754065.1		n.229+314C>G		intron	N/A
ENSG00000298241	ENST00000754066.1		n.398+314C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000160

AC:

AN:

1123332

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

539386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23236

American (AMR)

AF:

0.00

AC:

AN:

10398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15332

East Asian (EAS)

AF:

0.00

AC:

AN:

26676

South Asian (SAS)

AF:

0.00

AC:

AN:

33960

European-Finnish (FIN)

AF:

0.0000419

AC:

AN:

23856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3034

European-Non Finnish (NFE)

AF:

0.0000170

AC:

AN:

941750

Other (OTH)

AF:

0.0000222

AC:

AN:

45090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000199

AC:

AN:

150994

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73714

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41290

American (AMR)

AF:

0.00

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

67680

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

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

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.11

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.0

PhyloP100

1.7

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.20

REVEL

Benign

0.072

Sift

Benign

0.46

Sift4G

Benign

0.51

Polyphen

0.26

Vest4

0.044

MutPred

0.13

Gain of MoRF binding (P = 0.0286)

MVP

0.12

MPC

0.62

ClinPred

0.35

GERP RS

0.67

Varity_R

0.061

gMVP

0.49

Mutation Taster

=90/10

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