9-116187201-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002581.5(PAPPA):c.463G>A(p.Val155Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,106 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (79 hom.)
• Consequence: PAPPA NM_002581.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.44

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006983906).
• BP6: Variant 9-116187201-G-A is Benign according to our data. Variant chr9-116187201-G-A is described in ClinVar as [Benign]. Clinvar id is 788594.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0034 (517/152248) while in subpopulation AMR AF= 0.0288 (441/15298). AF 95% confidence interval is 0.0266. There are 8 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 518 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPPA	NM_002581.5	c.463G>A	p.Val155Met	missense_variant	2/22	ENST00000328252.4
PAPPA	XM_017014784.3	c.463G>A	p.Val155Met	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPPA	ENST00000328252.4	c.463G>A	p.Val155Met	missense_variant	2/22	1	NM_002581.5	P1

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 518 AN: 152130 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00768 AC: 1930 AN: 251366 Hom.: 65 AF XY: 0.00562 AC XY: 764 AN XY: 135876

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00176 AC: 2567 AN: 1461858 Hom.: 79 Cov.: 32 AF XY: 0.00145 AC XY: 1054 AN XY: 727238

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.0491

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00340 AC: 517 AN: 152248 Hom.: 8 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74430

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000504 Hom.: 1

Bravo AF: 0.00575

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00574 AC: 697

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.65	D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.096
Sift	Benign	0.087	T
Sift4G	Benign	0.17	T
Polyphen		0.049	B
Vest4		0.15
MVP		0.13
MPC		1.0
ClinPred		0.016	T
GERP RS		3.0
Varity_R		0.039
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs146292613; hg19: chr9-118949480; COSMIC: COSV60284075;