Genetic Variant NM_002581.5:c.259A>G (chr9-116154431-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_002581.5(PAPPA):c.259A>G(p.Thr87Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PAPPA
NM_002581.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.80

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.055845827).

BP6

Variant 9-116154431-A-G is Benign according to our data. Variant chr9-116154431-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2522009.Status of the report is criteria_provided_single_submitter, 1 stars.

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.259A>G	p.Thr87Ala	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.259A>G	p.Thr87Ala	missense	Exon 1 of 22	ENSP00000330658.3	Q13219
ENSG00000298241	ENST00000754065.1		n.229+320T>C		intron	N/A
ENSG00000298241	ENST00000754066.1		n.398+320T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150436

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1113736

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

534766

African (AFR)

AF:

0.00

AC:

AN:

23020

American (AMR)

AF:

0.00

AC:

AN:

10390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15240

East Asian (EAS)

AF:

0.00

AC:

AN:

26578

South Asian (SAS)

AF:

0.00

AC:

AN:

33078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3006

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

934114

Other (OTH)

AF:

0.00

AC:

AN:

44732

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

150436

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73454

African (AFR)

AF:

0.00

AC:

AN:

41182

American (AMR)

AF:

0.00

AC:

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.00

AC:

AN:

5032

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67542

Other (OTH)

AF:

0.00

AC:

AN:

2064

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.054

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.15

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.19

M_CAP

Benign

0.076

MetaRNN

Benign

0.056

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

PhyloP100

1.8

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.28

REVEL

Benign

0.033

Sift

Benign

0.81

Sift4G

Benign

0.87

Polyphen

0.0

Vest4

0.042

MutPred

0.17

Loss of phosphorylation at T87 (P = 0.0016)

MVP

0.068

MPC

0.35

ClinPred

0.044

GERP RS

0.52

Varity_R

0.044

gMVP

0.35

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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