9-116301768-C-T

Position:

• chr9-116301768-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
PAPPA	NM_002581.5	c.2954-989C>T		intron_variant		ENST00000328252.4
PAPPA-AS2	NR_170222.1	n.534-12876G>A		intron_variant, non_coding_transcript_variant
PAPPA	XM_006717129.4	c.860-989C>T		intron_variant
PAPPA	XM_017014784.3	c.2954-989C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPPA	ENST00000328252.4	c.2954-989C>T		intron_variant		1	NM_002581.5	P1
	ENST00000451100.1	n.454-12876G>A		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.0702

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0258

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.137

Alfa AF: 0.177 Hom.: 1268

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

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: rs10513272; hg19: chr9-119064047;