rs3824474

Positions:

• chr9-76157202-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372043.1(PCSK5):​c.1430+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0682 in 1,338,672 control chromosomes in the GnomAD database, including 7,068 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 0.13 (2143 hom., cov: 32)
  • Exomes 𝑓: 0.061 (4925 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85

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]

PCSK5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.1430+40A>G		intron_variant		ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.1430+40A>G		intron_variant			NM_001372043.1	ENSP00000500971.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19076 AN: 151988 Hom.: 2124 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0547

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.0966 AC: 23857 AN: 246920 Hom.: 2115 AF XY: 0.0878 AC XY: 11725 AN XY: 133594

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.0262

Gnomad EAS exome AF: 0.262

Gnomad SAS exome AF: 0.0945

Gnomad FIN exome AF: 0.0507

Gnomad NFE exome AF: 0.0359

Gnomad OTH exome AF: 0.0709

GnomAD4 exome AF: 0.0608 AC: 72094 AN: 1186566 Hom.: 4925 Cov.: 16 AF XY: 0.0602 AC XY: 36276 AN XY: 603040

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.297

Gnomad4 SAS exome AF: 0.0931

Gnomad4 FIN exome AF: 0.0477

Gnomad4 NFE exome AF: 0.0353

Gnomad4 OTH exome AF: 0.0736

GnomAD4 genome AF: 0.126 AC: 19138 AN: 152106 Hom.: 2143 Cov.: 32 AF XY: 0.127 AC XY: 9476 AN XY: 74380

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0547

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0744 Hom.: 194

Bravo AF: 0.140

Asia WGS AF: 0.212 AC: 739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.5
DANN	Benign	0.32

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: rs3824474; hg19: chr9-78772118;