rs1405

Variant names:

• chr9-116192345-A-G
• rs1405
• NM_002581.5:c.1478+4129A>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.1478+4129A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 151,996 control chromosomes in the GnomAD database, including 18,372 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 0.45 (18372 hom., cov: 31)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.352
• Publications: 10 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.607 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA	NM_002581.5	MANE Select	c.1478+4129A>G		intron	N/A	NP_002572.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA	ENST00000328252.4	TSL:1 MANE Select	c.1478+4129A>G		intron	N/A	ENSP00000330658.3	Q13219

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68427 AN: 151878 Hom.: 18373 Cov.: 31

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.435

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

GnomAD4 genome AF: 0.450 AC: 68446 AN: 151996 Hom.: 18372 Cov.: 31 AF XY: 0.447 AC XY: 33230 AN XY: 74296

African (AFR) AF: 0.185 AC: 7663 AN: 41472

American (AMR) AF: 0.379 AC: 5795 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1575 AN: 3468

East Asian (EAS) AF: 0.208 AC: 1071 AN: 5152

South Asian (SAS) AF: 0.416 AC: 1999 AN: 4810

European-Finnish (FIN) AF: 0.663 AC: 7010 AN: 10566

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41595 AN: 67942

Other (OTH) AF: 0.433 AC: 914 AN: 2110

Alfa AF: 0.549 Hom.: 92780

Bravo AF: 0.417

Asia WGS AF: 0.323 AC: 1124 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.96
DANN	Benign	0.72
PhyloP100		-0.35
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: rs1405; hg19: chr9-118954624;