rs3824474

Variant names:

• chr9-76157202-A-G
• rs3824474
• NM_001372043.1:c.1430+40A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• syndromic congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372043.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	NM_001372043.1	MANE Select	c.1430+40A>G		intron	N/A	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.1430+40A>G		intron	N/A	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.1430+40A>G		intron	N/A	NP_006191.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.1430+40A>G		intron	N/A	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.1430+40A>G		intron	N/A	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.1430+40A>G		intron	N/A	ENSP00000524257.1

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

GnomAD2 exomes AF: 0.0966 AC: 23857 AN: 246920 AF XY: 0.0878

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 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

African (AFR) AF: 0.284 AC: 8078 AN: 28402

American (AMR) AF: 0.171 AC: 7570 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 602 AN: 24332

East Asian (EAS) AF: 0.297 AC: 11440 AN: 38462

South Asian (SAS) AF: 0.0931 AC: 7533 AN: 80872

European-Finnish (FIN) AF: 0.0477 AC: 2476 AN: 51906

Middle Eastern (MID) AF: 0.0473 AC: 189 AN: 3994

European-Non Finnish (NFE) AF: 0.0353 AC: 30436 AN: 863048

Other (OTH) AF: 0.0736 AC: 3770 AN: 51226

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

African (AFR) AF: 0.280 AC: 11616 AN: 41452

American (AMR) AF: 0.138 AC: 2114 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 105 AN: 3464

East Asian (EAS) AF: 0.276 AC: 1419 AN: 5148

South Asian (SAS) AF: 0.103 AC: 497 AN: 4822

European-Finnish (FIN) AF: 0.0547 AC: 581 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2543 AN: 67992

Other (OTH) AF: 0.114 AC: 241 AN: 2112

Alfa AF: 0.0790 Hom.: 224

Bravo AF: 0.140

Asia WGS AF: 0.212 AC: 739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.5
DANN	Benign	0.32
PhyloP100		1.8
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: rs3824474; hg19: chr9-78772118;