9-116312558-A-G

Variant names:

• chr9-116312558-A-G
• rs2418441
• NM_002581.5:c.3147+9608A>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.3147+9608A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.917 in 151,998 control chromosomes in the GnomAD database, including 65,050 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 0.92 (65050 hom., cov: 32)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.345
• Publications: 3 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]

ENSG00000244757 (HGNC:):

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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPPA	NM_002581.5	c.3147+9608A>G		intron_variant	Intron 10 of 21	ENST00000328252.4	NP_002572.2
PAPPA-AS2	NR_170222.1	n.533+5700T>C		intron_variant	Intron 4 of 5
PAPPA	XM_017014784.3	c.3147+9608A>G		intron_variant	Intron 10 of 20		XP_016870273.1
PAPPA	XM_006717129.4	c.1053+9608A>G		intron_variant	Intron 6 of 17		XP_006717192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4	c.3147+9608A>G		intron_variant	Intron 10 of 21	1	NM_002581.5	ENSP00000330658.3
ENSG00000244757	ENST00000451100.1	n.453+3756T>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.918 AC: 139373 AN: 151880 Hom.: 65029 Cov.: 32

Gnomad AFR AF: 0.729

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.972

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.988

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.994

Gnomad OTH AF: 0.931

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

GnomAD4 genome AF: 0.917 AC: 139448 AN: 151998 Hom.: 65050 Cov.: 32 AF XY: 0.921 AC XY: 68448 AN XY: 74338

African (AFR) AF: 0.728 AC: 30122 AN: 41350

American (AMR) AF: 0.961 AC: 14697 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.972 AC: 3368 AN: 3464

East Asian (EAS) AF: 0.999 AC: 5136 AN: 5142

South Asian (SAS) AF: 0.988 AC: 4765 AN: 4822

European-Finnish (FIN) AF: 0.999 AC: 10610 AN: 10616

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.994 AC: 67594 AN: 68000

Other (OTH) AF: 0.932 AC: 1966 AN: 2110

Alfa AF: 0.885 Hom.: 23141

Bravo AF: 0.906

Asia WGS AF: 0.973 AC: 3386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.62
PhyloP100		0.34
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: rs2418441; hg19: chr9-119074837;