9-116360063-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPPA	NM_002581.5	c.4348-2529C>T		intron_variant	Intron 17 of 21	ENST00000328252.4	NP_002572.2
PAPPA	XM_017014784.3	c.4234-2529C>T		intron_variant	Intron 16 of 20		XP_016870273.1
PAPPA	XM_006717129.4	c.2254-2529C>T		intron_variant	Intron 13 of 17		XP_006717192.1
PAPPA-AS2	NR_170222.1	n.80+3534G>A		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4	c.4348-2529C>T		intron_variant	Intron 17 of 21	1	NM_002581.5	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

Gnomad4 AFR AF: 0.507

Gnomad4 AMR AF: 0.707

Gnomad4 ASJ AF: 0.735

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.741

Gnomad4 FIN AF: 0.725

Gnomad4 NFE AF: 0.716

Gnomad4 OTH AF: 0.682

Alfa AF: 0.708 Hom.: 47646

Bravo AF: 0.651

Asia WGS AF: 0.676 AC: 2349 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.52

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: rs751543; hg19: chr9-119122342; COSMIC: COSV60287227;