9-116154437-G-A

Variant names:

• chr9-116154437-G-A
• rs915528378
• NM_002581.5:c.265G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002581.5(PAPPA):​c.265G>A​(p.Glu89Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000235 in 1,274,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E89Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: PAPPA NM_002581.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 0 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]

ENSG00000298241 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0636639).

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.265G>A	p.Glu89Lys	missense	Exon 1 of 22	NP_002572.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPPA	ENST00000328252.4	TSL:1 MANE Select	c.265G>A	p.Glu89Lys	missense	Exon 1 of 22	ENSP00000330658.3	Q13219
	ENSG00000298241	ENST00000754065.1		n.229+314C>T		intron	N/A
	ENSG00000298241	ENST00000754066.1		n.398+314C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 150994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.90e-7 AC: 1 AN: 1123332 Hom.: 0 Cov.: 27 AF XY: 0.00000185 AC XY: 1 AN XY: 539386

African (AFR) AF: 0.00 AC: 0 AN: 23236

American (AMR) AF: 0.00 AC: 0 AN: 10398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15332

East Asian (EAS) AF: 0.00 AC: 0 AN: 26676

South Asian (SAS) AF: 0.00 AC: 0 AN: 33960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3034

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 941750

Other (OTH) AF: 0.00 AC: 0 AN: 45090

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 150994 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73714

African (AFR) AF: 0.00 AC: 0 AN: 41290

American (AMR) AF: 0.00 AC: 0 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67680

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.052
Sift	Benign	0.70	T
Sift4G	Benign	0.58	T
Polyphen		0.067	B
Vest4		0.084
MutPred		0.21		Gain of ubiquitination at E89 (P = 0.0037)
MVP		0.082
MPC		0.60
ClinPred		0.084	T
GERP RS		0.67
Varity_R		0.054
gMVP		0.50
Mutation Taster		=92/8	polymorphism

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: rs915528378; hg19: chr9-118916716;