9-116301768-C-T

Variant names:

• chr9-116301768-C-T
• rs10513272
• NM_002581.5:c.2954-989C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002581.5(PAPPA):​c.2954-989C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 152,124 control chromosomes in the GnomAD database, including 2,228 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 0.15 (2228 hom., cov: 32)
• Consequence: PAPPA NM_002581.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 3 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]

ENSG00000244757 (HGNC:):

PAPPA-AS2 (HGNC:35160): (PAPPA antisense RNA 2)

ACMG classification

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 = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPPA	NM_002581.5	c.2954-989C>T		intron_variant	Intron 9 of 21	ENST00000328252.4	NP_002572.2
PAPPA-AS2	NR_170222.1	n.534-12876G>A		intron_variant	Intron 4 of 5
PAPPA	XM_017014784.3	c.2954-989C>T		intron_variant	Intron 9 of 20		XP_016870273.1
PAPPA	XM_006717129.4	c.860-989C>T		intron_variant	Intron 5 of 17		XP_006717192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPPA	ENST00000328252.4	c.2954-989C>T		intron_variant	Intron 9 of 21	1	NM_002581.5	ENSP00000330658.3
ENSG00000244757	ENST00000451100.1	n.454-12876G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23282 AN: 152006 Hom.: 2228 Cov.: 32

Gnomad AFR AF: 0.0700

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.138

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.153 AC: 23292 AN: 152124 Hom.: 2228 Cov.: 32 AF XY: 0.148 AC XY: 11020 AN XY: 74362

African (AFR) AF: 0.0702 AC: 2913 AN: 41522

American (AMR) AF: 0.125 AC: 1906 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0258 AC: 124 AN: 4804

European-Finnish (FIN) AF: 0.205 AC: 2162 AN: 10566

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15002 AN: 67982

Other (OTH) AF: 0.137 AC: 289 AN: 2110

Alfa AF: 0.172 Hom.: 1866

Bravo AF: 0.144

Asia WGS AF: 0.0260 AC: 92 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	0.32
DANN	Benign	0.65
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs10513272; hg19: chr9-119064047;