rs7020782

Variant names:

• chr9-116344602-C-A
• rs7020782
• NM_002581.5:c.3671C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002581.5(PAPPA):​c.3671C>A​(p.Ser1224Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 1,613,674 control chromosomes in the GnomAD database, including 378,522 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (29221 hom., cov: 32)
  • Exomes 𝑓: 0.69 (349301 hom.)
• Consequence: PAPPA NM_002581.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.765
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4816685E-6).
• BP6: Variant 9-116344602-C-A is Benign according to our data. Variant chr9-116344602-C-A is described in ClinVar as Benign. ClinVar VariationId is 1238296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 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.3671C>A	p.Ser1224Tyr	missense	Exon 14 of 22	NP_002572.2
	PAPPA-AS2	NR_170222.1		n.80+18995G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA	ENST00000328252.4	TSL:1 MANE Select	c.3671C>A	p.Ser1224Tyr	missense	Exon 14 of 22	ENSP00000330658.3

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90779 AN: 151936 Hom.: 29229 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.692

Gnomad FIN AF: 0.743

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.615

GnomAD2 exomes AF: 0.676 AC: 169608 AN: 251038 AF XY: 0.683

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.698

Gnomad FIN exome AF: 0.729

Gnomad NFE exome AF: 0.699

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.688 AC: 1005986 AN: 1461620 Hom.: 349301 Cov.: 46 AF XY: 0.690 AC XY: 501652 AN XY: 727124

African (AFR) AF: 0.330 AC: 11043 AN: 33480

American (AMR) AF: 0.675 AC: 30167 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 18245 AN: 26130

East Asian (EAS) AF: 0.762 AC: 30249 AN: 39696

South Asian (SAS) AF: 0.709 AC: 61116 AN: 86252

European-Finnish (FIN) AF: 0.723 AC: 38628 AN: 53416

Middle Eastern (MID) AF: 0.740 AC: 4267 AN: 5768

European-Non Finnish (NFE) AF: 0.694 AC: 771589 AN: 1111770

Other (OTH) AF: 0.674 AC: 40682 AN: 60388

GnomAD4 genome AF: 0.597 AC: 90783 AN: 152054 Hom.: 29221 Cov.: 32 AF XY: 0.602 AC XY: 44716 AN XY: 74330

African (AFR) AF: 0.332 AC: 13749 AN: 41454

American (AMR) AF: 0.665 AC: 10158 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2447 AN: 3472

East Asian (EAS) AF: 0.710 AC: 3660 AN: 5154

South Asian (SAS) AF: 0.691 AC: 3328 AN: 4816

European-Finnish (FIN) AF: 0.743 AC: 7854 AN: 10576

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.699 AC: 47551 AN: 67984

Other (OTH) AF: 0.615 AC: 1299 AN: 2112

Alfa AF: 0.670 Hom.: 100323

Bravo AF: 0.579

TwinsUK AF: 0.711 AC: 2636

ALSPAC AF: 0.687 AC: 2647

ESP6500AA AF: 0.338 AC: 1489

ESP6500EA AF: 0.699 AC: 6011

ExAC AF: 0.668 AC: 81169

Asia WGS AF: 0.649 AC: 2258 AN: 3478

EpiCase AF: 0.703

EpiControl AF: 0.711

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0000035	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.77
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.13
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.025	D
Polyphen		0.36	B
Vest4		0.10
MPC		0.46
ClinPred		0.0041	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.42
Mutation Taster		=96/4	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: rs7020782; hg19: chr9-119106881; COSMIC: COSV60278697;