rs902947256

Variant names:

• chr9-116154303-C-A
• rs902947256
• NM_002581.5:c.131C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-116154303-C-A
• chr9-116154303-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002581.5(PAPPA):​c.131C>A​(p.Pro44Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 145,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P44R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAPPA NM_002581.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.967
• Publications: 0 publications found

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]

ENSG00000298241 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16218615).

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>A	p.Pro44Gln	missense	Exon 1 of 22	NP_002572.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA	ENST00000328252.4	TSL:1 MANE Select	c.131C>A	p.Pro44Gln	missense	Exon 1 of 22	ENSP00000330658.3	Q13219
	ENSG00000298241	ENST00000754065.1		n.229+448G>T		intron	N/A
	ENSG00000298241	ENST00000754066.1		n.398+448G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 145884 Hom.: 0 Cov.: 31

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: 0.000209

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: 0 AN: 780478 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 361762

African (AFR) AF: 0.00 AC: 0 AN: 14684

American (AMR) AF: 0.00 AC: 0 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4846

East Asian (EAS) AF: 0.00 AC: 0 AN: 3388

South Asian (SAS) AF: 0.00 AC: 0 AN: 15912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1526

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 713226

Other (OTH) AF: 0.00 AC: 0 AN: 25534

GnomAD4 genome AF: 0.00000685 AC: 1 AN: 145884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 70880

African (AFR) AF: 0.00 AC: 0 AN: 40748

American (AMR) AF: 0.00 AC: 0 AN: 14706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4988

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65758

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.97
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.054
Sift	Benign	0.068	T
Sift4G	Benign	0.12	T
Polyphen		0.86	P
Vest4		0.13
MutPred		0.18		Loss of loop (P = 0.0075)
MVP		0.068
MPC		0.33
ClinPred		0.76	D
GERP RS		2.3
Varity_R		0.050
gMVP		0.48
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs902947256; hg19: chr9-118916582;