rs13290387

Positions:

• chr9-116227647-G-C

Variant summary

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

The NM_002581.5(PAPPA):​c.2233+95G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 1,303,622 control chromosomes in the GnomAD database, including 217,832 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 0.54 (22409 hom., cov: 32)
  • Exomes 𝑓: 0.58 (195423 hom.)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.463

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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPPA	NM_002581.5	c.2233+95G>C		intron_variant		ENST00000328252.4	NP_002572.2
PAPPA	XM_006717129.4	c.139+95G>C		intron_variant			XP_006717192.1
PAPPA	XM_017014784.3	c.2233+95G>C		intron_variant			XP_016870273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4	c.2233+95G>C		intron_variant		1	NM_002581.5	ENSP00000330658	P1

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81259 AN: 151910 Hom.: 22382 Cov.: 32

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.505

GnomAD4 exome AF: 0.577 AC: 663947 AN: 1151594 Hom.: 195423 AF XY: 0.574 AC XY: 327603 AN XY: 570432

Gnomad4 AFR exome AF: 0.488

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.576

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.488

Gnomad4 FIN exome AF: 0.650

Gnomad4 NFE exome AF: 0.603

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.535 AC: 81335 AN: 152028 Hom.: 22409 Cov.: 32 AF XY: 0.531 AC XY: 39460 AN XY: 74304

Gnomad4 AFR AF: 0.483

Gnomad4 AMR AF: 0.416

Gnomad4 ASJ AF: 0.582

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.654

Gnomad4 NFE AF: 0.599

Gnomad4 OTH AF: 0.502

Alfa AF: 0.576 Hom.: 3206

Bravo AF: 0.512

Asia WGS AF: 0.397 AC: 1383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.21
DANN	Benign	0.55

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: rs13290387; hg19: chr9-118989926; COSMIC: COSV60284922;