rs3830384

Positions:

• chr9-76189290-G-GAAAAT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001372043.1(PCSK5):​c.2510+70_2510+74dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,323,028 control chromosomes in the GnomAD database, including 68,348 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7372 hom., cov: 17)
  • Exomes 𝑓: 0.31 (60976 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.678

Genes affected

PCSK5 (HGNC:8747): (proprotein convertase subtilisin/kexin type 5) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER. It then sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. This encoded protein is widely expressed and one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It mediates posttranslational endoproteolytic processing for several integrin alpha subunits and is thought to process prorenin, pro-membrane type-1 matrix metalloproteinase and HIV-1 glycoprotein gp160. Alternative splicing results in multiple transcript variants, some of which encode distinct isoforms, including a protease packaged into dense core granules (PC5A) and a type 1 membrane bound protease (PC5B). [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.2510+70_2510+74dup		intron_variant		ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.2510+70_2510+74dup		intron_variant			NM_001372043.1	ENSP00000500971	A2

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45744 AN: 151724 Hom.: 7368 Cov.: 17

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.307 AC: 359946 AN: 1171184 Hom.: 60976 AF XY: 0.309 AC XY: 183087 AN XY: 593410

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.284

Gnomad4 EAS exome AF: 0.566

Gnomad4 SAS exome AF: 0.348

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.314

GnomAD4 genome AF: 0.301 AC: 45760 AN: 151844 Hom.: 7372 Cov.: 17 AF XY: 0.305 AC XY: 22665 AN XY: 74204

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.591

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.314

Gnomad4 OTH AF: 0.324

Alfa AF: 0.314 Hom.: 817

Asia WGS AF: 0.477 AC: 1658 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3830384; hg19: chr9-78804206;