rs7869550

chr9-116372517-A-G

Variant summary

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

The NM_002581.5(PAPPA):c.4605+4763A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,164 control chromosomes in the GnomAD database, including 1,852 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 0.14 (1852 hom., cov: 32)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.721

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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPPA	NM_002581.5	c.4605+4763A>G		intron_variant		ENST00000328252.4
PAPPA	XM_006717129.4	c.2511+4763A>G		intron_variant
PAPPA	XM_017014784.3	c.4491+4763A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPPA	ENST00000328252.4	c.4605+4763A>G		intron_variant		1	NM_002581.5	P1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 21983 AN: 152046 Hom.: 1849 Cov.: 32

Gnomad AFR AF: 0.0936

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.0927

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.128

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

GnomAD4 genome AF: 0.145 AC: 22003 AN: 152164 Hom.: 1852 Cov.: 32 AF XY: 0.141 AC XY: 10497 AN XY: 74386

Gnomad4 AFR AF: 0.0938

Gnomad4 AMR AF: 0.0925

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.126

Alfa AF: 0.176 Hom.: 3216

Bravo AF: 0.136

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	14
Dann	Benign	0.87

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: rs7869550; hg19: chr9-119134796;