Genetic Variant NM_002581.5:c.2233+95G>C (chr9-116227647-G-C) – 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.2233+95G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 1,303,622 control chromosomes in the GnomAD database, including 217,832 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 0.54 ( 22409 hom., cov: 32)

Exomes 𝑓: 0.58 ( 195423 hom. )

Consequence

PAPPA
NM_002581.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.463

Publications

7 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=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PAPPA	NM_002581.5 link	c.2233+95G>C	intron_variant	Intron 6 of 21	ENST00000328252.4	NP_002572.2	Q13219Q7Z613B4DTA8
PAPPA	XM_017014784.3 link	c.2233+95G>C	intron_variant	Intron 6 of 20		XP_016870273.1
PAPPA	XM_006717129.4 link	c.139+95G>C	intron_variant	Intron 2 of 17		XP_006717192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4 link	c.2233+95G>C		intron_variant	Intron 6 of 21	1	NM_002581.5	ENSP00000330658.3		Q13219

Frequencies

GnomAD3 genomes

AF:

0.535

AC:

81259

AN:

151910

Hom.:

22382

Cov.:

show subpopulations

Gnomad AFR

AF:

0.483

Gnomad AMI

AF:

0.608

Gnomad AMR

AF:

0.415

Gnomad ASJ

AF:

0.582

Gnomad EAS

AF:

0.267

Gnomad SAS

AF:

0.450

Gnomad FIN

AF:

0.654

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.599

Gnomad OTH

AF:

0.505

GnomAD4 exome

AF:

0.577

AC:

663947

AN:

1151594

Hom.:

195423

AF XY:

0.574

AC XY:

327603

AN XY:

570432

show subpopulations

African (AFR)

AF:

0.488

AC:

12760

AN:

26148

American (AMR)

AF:

0.364

AC:

9173

AN:

25230

Ashkenazi Jewish (ASJ)

AF:

0.576

AC:

11389

AN:

19768

East Asian (EAS)

AF:

0.226

AC:

7862

AN:

34718

South Asian (SAS)

AF:

0.488

AC:

31500

AN:

64592

European-Finnish (FIN)

AF:

0.650

AC:

23621

AN:

36360

Middle Eastern (MID)

AF:

0.558

AC:

2711

AN:

4860

European-Non Finnish (NFE)

AF:

0.603

AC:

537259

AN:

890598

Other (OTH)

AF:

0.561

AC:

27672

AN:

49320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

13116

26232

39349

52465

65581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14052

28104

42156

56208

70260

<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:

0.535

AC:

81335

AN:

152028

Hom.:

22409

Cov.:

AF XY:

0.531

AC XY:

39460

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.483

AC:

20031

AN:

41444

American (AMR)

AF:

0.416

AC:

6344

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

2018

AN:

3468

East Asian (EAS)

AF:

0.267

AC:

1382

AN:

5180

South Asian (SAS)

AF:

0.452

AC:

2174

AN:

4810

European-Finnish (FIN)

AF:

0.654

AC:

6912

AN:

10576

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.599

AC:

40705

AN:

67968

Other (OTH)

AF:

0.502

AC:

1059

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1920

3839

5759

7678

9598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.576

Hom.:

3206

Bravo

AF:

0.512

Asia WGS

AF:

0.397

AC:

1383

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.21

(source)

DANN

Benign

0.55

PhyloP100

-0.46

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