rs7020782

Positions:

• chr9-116344602-C-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPPA	NM_002581.5	c.3671C>A	p.Ser1224Tyr	missense_variant	14/22	ENST00000328252.4	NP_002572.2
PAPPA	XM_017014784.3	c.3557C>A	p.Ser1186Tyr	missense_variant	13/21		XP_016870273.1
PAPPA	XM_006717129.4	c.1577C>A	p.Ser526Tyr	missense_variant	10/18		XP_006717192.1
PAPPA-AS2	NR_170222.1	n.80+18995G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4	c.3671C>A	p.Ser1224Tyr	missense_variant	14/22	1	NM_002581.5	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

GnomAD3 exomes AF: 0.676 AC: 169608 AN: 251038 Hom.: 58597 AF XY: 0.683 AC XY: 92637 AN XY: 135650

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 SAS exome AF: 0.711

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

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.675

Gnomad4 ASJ exome AF: 0.698

Gnomad4 EAS exome AF: 0.762

Gnomad4 SAS exome AF: 0.709

Gnomad4 FIN exome AF: 0.723

Gnomad4 NFE exome AF: 0.694

Gnomad4 OTH exome AF: 0.674

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

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.665

Gnomad4 ASJ AF: 0.705

Gnomad4 EAS AF: 0.710

Gnomad4 SAS AF: 0.691

Gnomad4 FIN AF: 0.743

Gnomad4 NFE AF: 0.699

Gnomad4 OTH AF: 0.615

Alfa AF: 0.678 Hom.: 71182

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 26122709, 25745440, 16540175, 31519945) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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
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

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: rs7020782; hg19: chr9-119106881; COSMIC: COSV60278697;