rs1888636

chr9-116177055-T-Achr9-116177055-T-G

Variant summary

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

The NM_002581.5(PAPPA):c.416-10099T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 151,642 control chromosomes in the GnomAD database, including 17,999 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 0.44 (17999 hom., cov: 29)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.634

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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPPA	NM_002581.5	c.416-10099T>A		intron_variant		ENST00000328252.4
PAPPA	XM_017014784.3	c.416-10099T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPPA	ENST00000328252.4	c.416-10099T>A		intron_variant		1	NM_002581.5	P1

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67001 AN: 151520 Hom.: 18002 Cov.: 29

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.427

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

GnomAD4 genome AF: 0.442 AC: 67019 AN: 151642 Hom.: 17999 Cov.: 29 AF XY: 0.439 AC XY: 32505 AN XY: 74082

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.661

Gnomad4 NFE AF: 0.610

Gnomad4 OTH AF: 0.426

Alfa AF: 0.523 Hom.: 2812

Bravo AF: 0.407

Asia WGS AF: 0.320 AC: 1115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.75
Dann	Benign	0.45

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: rs1888636; hg19: chr9-118939334;