rs7869550

Variant names:

• chr9-116372517-A-G
• rs7869550
• NM_002581.5:c.4605+4763A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PAPPA	NM_002581.5	c.4605+4763A>G		intron_variant	Intron 19 of 21	ENST00000328252.4	NP_002572.2
PAPPA	XM_017014784.3	c.4491+4763A>G		intron_variant	Intron 18 of 20		XP_016870273.1
PAPPA	XM_006717129.4	c.2511+4763A>G		intron_variant	Intron 15 of 17		XP_006717192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4	c.4605+4763A>G		intron_variant	Intron 19 of 21	1	NM_002581.5	ENSP00000330658.3

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

African (AFR) AF: 0.0938 AC: 3895 AN: 41512

American (AMR) AF: 0.0925 AC: 1415 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4826

European-Finnish (FIN) AF: 0.211 AC: 2236 AN: 10580

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13110 AN: 67998

Other (OTH) AF: 0.126 AC: 266 AN: 2108

Alfa AF: 0.166 Hom.: 4877

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
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

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: rs7869550; hg19: chr9-119134796;