rs10817882

Positions:

• chr9-116383462-C-T

Variant summary

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

The NM_002581.5(PAPPA):​c.4776+969C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 152,134 control chromosomes in the GnomAD database, including 45,265 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 0.77 (45265 hom., cov: 32)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0730

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPPA	NM_002581.5	c.4776+969C>T		intron_variant		ENST00000328252.4	NP_002572.2
PAPPA	XM_017014784.3	c.4662+969C>T		intron_variant			XP_016870273.1
PAPPA	XM_006717129.4	c.2682+969C>T		intron_variant			XP_006717192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4	c.4776+969C>T		intron_variant		1	NM_002581.5	ENSP00000330658.3
PAPPA	ENST00000483254.1	n.682+969C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116953 AN: 152014 Hom.: 45237 Cov.: 32

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.779

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.769 AC: 117044 AN: 152134 Hom.: 45265 Cov.: 32 AF XY: 0.768 AC XY: 57098 AN XY: 74380

Gnomad4 AFR AF: 0.846

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.762

Gnomad4 EAS AF: 0.618

Gnomad4 SAS AF: 0.716

Gnomad4 FIN AF: 0.757

Gnomad4 NFE AF: 0.742

Gnomad4 OTH AF: 0.775

Alfa AF: 0.746 Hom.: 7197

Bravo AF: 0.773

Asia WGS AF: 0.662 AC: 2304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.0
DANN	Benign	0.78

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: rs10817882; hg19: chr9-119145741;