9-75956588-A-G

Variant names:

• chr9-75956588-A-G
• rs1340503
• NM_001372043.1:c.297+24105A>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.297+24105A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,086 control chromosomes in the GnomAD database, including 6,454 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 0.29 (6454 hom., cov: 32)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309
• Publications: 7 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]

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 (EAS) allele frequency at 95% confidence interval = 0.324 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	NM_001372043.1	MANE Select	c.297+24105A>G		intron	N/A	NP_001358972.1
	PCSK5	NM_001190482.2		c.297+24105A>G		intron	N/A	NP_001177411.1
	PCSK5	NM_006200.6		c.297+24105A>G		intron	N/A	NP_006191.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.297+24105A>G		intron	N/A	ENSP00000500971.1
	PCSK5	ENST00000376752.9	TSL:1	c.297+24105A>G		intron	N/A	ENSP00000365943.4
	PCSK5	ENST00000545128.5	TSL:5	c.297+24105A>G		intron	N/A	ENSP00000446280.1

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43910 AN: 151966 Hom.: 6449 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.283

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

GnomAD4 genome AF: 0.289 AC: 43912 AN: 152086 Hom.: 6454 Cov.: 32 AF XY: 0.289 AC XY: 21463 AN XY: 74336

African (AFR) AF: 0.257 AC: 10669 AN: 41478

American (AMR) AF: 0.266 AC: 4064 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1022 AN: 3466

East Asian (EAS) AF: 0.337 AC: 1741 AN: 5170

South Asian (SAS) AF: 0.307 AC: 1479 AN: 4816

European-Finnish (FIN) AF: 0.285 AC: 3012 AN: 10576

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21045 AN: 67996

Other (OTH) AF: 0.288 AC: 607 AN: 2108

Alfa AF: 0.303 Hom.: 18289

Bravo AF: 0.284

Asia WGS AF: 0.315 AC: 1096 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	9.7
DANN	Benign	0.89
PhyloP100		0.31
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: rs1340503; hg19: chr9-78571504; COSMIC: COSV65085842;