chr9-116154338-C-G

Variant names:

• chr9-116154338-C-G
• rs1485228405
• NM_002581.5:c.166C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002581.5(PAPPA):​c.166C>G​(p.Arg56Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000847 in 826,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: PAPPA NM_002581.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0905256).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.166C>G	p.Arg56Gly	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.166C>G	p.Arg56Gly	missense	Exon 1 of 22	ENSP00000330658.3	Q13219
	ENSG00000298241	ENST00000754065.1		n.229+413G>C		intron	N/A
	ENSG00000298241	ENST00000754066.1		n.398+413G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000139 AC: 2 AN: 144116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000253

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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000732 AC: 5 AN: 682814 Hom.: 0 Cov.: 9 AF XY: 0.00000946 AC XY: 3 AN XY: 317280

African (AFR) AF: 0.00 AC: 0 AN: 12448

American (AMR) AF: 0.00 AC: 0 AN: 774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4284

East Asian (EAS) AF: 0.00 AC: 0 AN: 2776

South Asian (SAS) AF: 0.00 AC: 0 AN: 13272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 332

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

European-Non Finnish (NFE) AF: 0.00000799 AC: 5 AN: 625460

Other (OTH) AF: 0.00 AC: 0 AN: 22156

GnomAD4 genome AF: 0.0000139 AC: 2 AN: 144116 Hom.: 0 Cov.: 31 AF XY: 0.0000285 AC XY: 2 AN XY: 70070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000253 AC: 1 AN: 39514

American (AMR) AF: 0.00 AC: 0 AN: 14358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 4922

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65714

Other (OTH) AF: 0.00 AC: 0 AN: 1990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.055
Sift	Uncertain	0.027	D
Sift4G	Benign	0.12	T
Polyphen		0.0030	B
Vest4		0.16
MutPred		0.24		Gain of relative solvent accessibility (P = 0.0275)
MVP		0.068
MPC		0.46
ClinPred		0.45	T
GERP RS		0.0070
Varity_R		0.089
gMVP		0.61
Mutation Taster		=84/16	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: rs1485228405; hg19: chr9-118916617;