9-116154329-C-T

Variant names:

• chr9-116154329-C-T
• rs1404330058
• NM_002581.5:c.157C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002581.5(PAPPA):​c.157C>T​(p.Arg53Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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. R53G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAPPA NM_002581.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23902935).

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.157C>T	p.Arg53Cys	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.157C>T	p.Arg53Cys	missense	Exon 1 of 22	ENSP00000330658.3	Q13219
	ENSG00000298241	ENST00000754065.1		n.229+422G>A		intron	N/A
	ENSG00000298241	ENST00000754066.1		n.398+422G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 694796 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 322614

African (AFR) AF: 0.00 AC: 0 AN: 12954

American (AMR) AF: 0.00 AC: 0 AN: 826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4334

East Asian (EAS) AF: 0.00 AC: 0 AN: 2920

South Asian (SAS) AF: 0.00 AC: 0 AN: 13874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 635666

Other (OTH) AF: 0.00 AC: 0 AN: 22650

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.23
MutPred		0.25		Loss of MoRF binding (P = 0.0175)
MVP		0.068
MPC		0.48
ClinPred		0.88	D
GERP RS		2.3
Varity_R		0.27
gMVP		0.61
Mutation Taster		=55/45	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: rs1404330058; hg19: chr9-118916608;