9-116360063-C-T

Variant names:

• chr9-116360063-C-T
• rs751543
• NM_002581.5:c.4348-2529C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002581.5(PAPPA):​c.4348-2529C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 152,146 control chromosomes in the GnomAD database, including 33,717 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 0.66 (33717 hom., cov: 34)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• Publications: 35 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]

PAPPA-AS2 (HGNC:35160): (PAPPA antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002581.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA	NM_002581.5	MANE Select	c.4348-2529C>T		intron	N/A	NP_002572.2
	PAPPA-AS2	NR_170222.1		n.80+3534G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA	ENST00000328252.4	TSL:1 MANE Select	c.4348-2529C>T		intron	N/A	ENSP00000330658.3

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100203 AN: 152028 Hom.: 33716 Cov.: 34

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.684

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

GnomAD4 genome AF: 0.659 AC: 100234 AN: 152146 Hom.: 33717 Cov.: 34 AF XY: 0.660 AC XY: 49071 AN XY: 74368

African (AFR) AF: 0.507 AC: 21053 AN: 41500

American (AMR) AF: 0.707 AC: 10806 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 2549 AN: 3470

East Asian (EAS) AF: 0.718 AC: 3706 AN: 5158

South Asian (SAS) AF: 0.741 AC: 3575 AN: 4826

European-Finnish (FIN) AF: 0.725 AC: 7679 AN: 10588

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48669 AN: 67990

Other (OTH) AF: 0.682 AC: 1441 AN: 2114

Alfa AF: 0.700 Hom.: 115011

Bravo AF: 0.651

Asia WGS AF: 0.676 AC: 2349 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.52
PhyloP100		-0.42
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: rs751543; hg19: chr9-119122342; COSMIC: COSV60287227;