rs3747823

chr9-116271191-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002581.5(PAPPA):c.2862-134G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 638,012 control chromosomes in the GnomAD database, including 14,201 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4416 hom., cov: 33)
  • Exomes 𝑓: 0.19 (9785 hom.)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.509

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPPA	NM_002581.5	c.2862-134G>A		intron_variant		ENST00000328252.4
PAPPA	XM_006717129.4	c.768-134G>A		intron_variant
PAPPA	XM_017014784.3	c.2862-134G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPPA	ENST00000328252.4	c.2862-134G>A		intron_variant		1	NM_002581.5	P1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34640 AN: 152004 Hom.: 4401 Cov.: 33

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.194

GnomAD4 exome AF: 0.189 AC: 91741 AN: 485892 Hom.: 9785 AF XY: 0.185 AC XY: 48107 AN XY: 259362

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.173

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.228 AC: 34690 AN: 152120 Hom.: 4416 Cov.: 33 AF XY: 0.228 AC XY: 16959 AN XY: 74344

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.191

Alfa AF: 0.206 Hom.: 447

Bravo AF: 0.244

Asia WGS AF: 0.191 AC: 665 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.4
Dann	Benign	0.30

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

Other links and lift over

dbSNP: rs3747823; hg19: chr9-119033470; COSMIC: COSV60279434;