Variant 9-116154378-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002581.5(PAPPA):c.206G>C(p.Trp69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,055,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PAPPA
NM_002581.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07931125).

BS2

High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPPA	NM_002581.5 linkuse as main transcript	c.206G>C	p.Trp69Ser	missense_variant	1/22	ENST00000328252.4
PAPPA	XM_017014784.3 linkuse as main transcript	c.206G>C	p.Trp69Ser	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPPA	ENST00000328252.4 linkuse as main transcript	c.206G>C	p.Trp69Ser	missense_variant	1/22	1	NM_002581.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000169

AC:

AN:

147780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000943

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

AF:

0.0000121

AC:

AN:

907924

Hom.:

Cov.:

AF XY:

0.00000919

AC XY:

AN XY:

435108

show subpopulations

Gnomad4 AFR exome

AF:

0.000164

Gnomad4 AMR exome

AF:

0.000719

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000838

GnomAD4 genome

AF:

0.000169

AC:

AN:

147780

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

71982

show subpopulations

Gnomad4 AFR

AF:

0.000269

Gnomad4 AMR

AF:

0.000943

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:

0.00

Bravo

AF:

0.000359

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 17, 2023

The c.206G>C (p.W69S) alteration is located in exon 1 (coding exon 1) of the PAPPA gene. This alteration results from a G to C substitution at nucleotide position 206, causing the tryptophan (W) at amino acid position 69 to be replaced by a serine (S). 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

0.095

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.094

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.37

M_CAP

Benign

0.060

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.88

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.35

REVEL

Benign

0.049

Sift

Benign

0.044

Sift4G

Benign

0.84

Polyphen

0.024

Vest4

0.39

MutPred

0.24

Loss of sheet (P = 0.0084);

MVP

0.068

MPC

0.58

ClinPred

0.14

GERP RS

0.32

Varity_R

0.13

gMVP

0.62

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