dbSNP rs3747823: PAPPA:c.2862-134G>A (chr9-116271191-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002581.5(PAPPA):c.2862-134G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 638,012 control chromosomes in the GnomAD database, including 14,201 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 0.23 ( 4416 hom., cov: 33)

Exomes 𝑓: 0.19 ( 9785 hom. )

Consequence

PAPPA
NM_002581.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.509

Publications

3 publications found

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PAPPA	NM_002581.5 link	c.2862-134G>A	intron_variant	Intron 8 of 21	ENST00000328252.4	NP_002572.2	Q13219Q7Z613B4DTA8
PAPPA	XM_017014784.3 link	c.2862-134G>A	intron_variant	Intron 8 of 20		XP_016870273.1
PAPPA	XM_006717129.4 link	c.768-134G>A	intron_variant	Intron 4 of 17		XP_006717192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4 link	c.2862-134G>A		intron_variant	Intron 8 of 21	1	NM_002581.5	ENSP00000330658.3		Q13219

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34640

AN:

152004

Hom.:

4401

Cov.:

show subpopulations

Gnomad AFR

AF:

0.321

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.149

Gnomad EAS

AF:

0.211

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.194

GnomAD4 exome

AF:

0.189

AC:

91741

AN:

485892

Hom.:

9785

AF XY:

0.185

AC XY:

48107

AN XY:

259362

show subpopulations

African (AFR)

AF:

0.313

AC:

4096

AN:

13070

American (AMR)

AF:

0.386

AC:

8396

AN:

21778

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

1996

AN:

14140

East Asian (EAS)

AF:

0.212

AC:

6974

AN:

32880

South Asian (SAS)

AF:

0.173

AC:

8106

AN:

46904

European-Finnish (FIN)

AF:

0.195

AC:

7714

AN:

39522

Middle Eastern (MID)

AF:

0.0999

AC:

359

AN:

3592

European-Non Finnish (NFE)

AF:

0.171

AC:

48954

AN:

286830

Other (OTH)

AF:

0.189

AC:

5146

AN:

27176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

3358

6716

10073

13431

16789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

478

956

1434

1912

2390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.228

AC:

34690

AN:

152120

Hom.:

4416

Cov.:

AF XY:

0.228

AC XY:

16959

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.321

AC:

13320

AN:

41494

American (AMR)

AF:

0.292

AC:

4459

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

516

AN:

3468

East Asian (EAS)

AF:

0.212

AC:

1094

AN:

5172

South Asian (SAS)

AF:

0.194

AC:

937

AN:

4828

European-Finnish (FIN)

AF:

0.191

AC:

2019

AN:

10566

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.173

AC:

11756

AN:

68006

Other (OTH)

AF:

0.191

AC:

404

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1330

2659

3989

5318

6648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

348

696

1044

1392

1740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.206

Hom.:

447

Bravo

AF:

0.244

Asia WGS

AF:

0.191

AC:

665

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.4

(source)

DANN

Benign

0.30

PhyloP100

0.51

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over