rs1353342

chr9-76259853-A-Cchr9-76259853-A-Gchr9-76259853-A-T

Variant summary

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

The NM_001372043.1(PCSK5):c.3142+19169A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.792 in 151,936 control chromosomes in the GnomAD database, including 49,172 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 0.79 (49172 hom., cov: 29)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK5	NM_001372043.1	c.3142+19169A>C		intron_variant		ENST00000674117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK5	ENST00000674117.1	c.3142+19169A>C		intron_variant			NM_001372043.1	A2
PCSK5	ENST00000424854.6	c.2161+19169A>C		intron_variant		5
PCSK5	ENST00000545128.5	c.3142+19169A>C		intron_variant		5		P4

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120230 AN: 151818 Hom.: 49141 Cov.: 29

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.877

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.882

Gnomad MID AF: 0.771

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.823

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

GnomAD4 genome AF: 0.792 AC: 120310 AN: 151936 Hom.: 49172 Cov.: 29 AF XY: 0.794 AC XY: 58992 AN XY: 74282

Gnomad4 AFR AF: 0.559

Gnomad4 AMR AF: 0.855

Gnomad4 ASJ AF: 0.877

Gnomad4 EAS AF: 0.910

Gnomad4 SAS AF: 0.828

Gnomad4 FIN AF: 0.882

Gnomad4 NFE AF: 0.887

Gnomad4 OTH AF: 0.823

Alfa AF: 0.867 Hom.: 79192

Bravo AF: 0.781

Asia WGS AF: 0.853 AC: 2965 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	0.65
Dann	Benign	0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1353342; hg19: chr9-78874769;