9-76100164-G-T

Variant summary

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

The NM_001372043.1(PCSK5):c.1107+4062G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 152,196 control chromosomes in the GnomAD database, including 611 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 0.083 (611 hom., cov: 32)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.591

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK5	NM_001372043.1	c.1107+4062G>T		intron_variant		ENST00000674117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK5	ENST00000674117.1	c.1107+4062G>T		intron_variant			NM_001372043.1	A2

Frequencies

GnomAD3 genomes AF: 0.0827 AC: 12576 AN: 152078 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0641

Gnomad ASJ AF: 0.0668

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0853

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0800

Gnomad OTH AF: 0.0760

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

GnomAD4 genome AF: 0.0827 AC: 12585 AN: 152196 Hom.: 611 Cov.: 32 AF XY: 0.0856 AC XY: 6369 AN XY: 74394

Gnomad4 AFR AF: 0.0746

Gnomad4 AMR AF: 0.0639

Gnomad4 ASJ AF: 0.0668

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0853

Gnomad4 NFE AF: 0.0800

Gnomad4 OTH AF: 0.0738

Alfa AF: 0.0749 Hom.: 697

Bravo AF: 0.0799

Asia WGS AF: 0.159 AC: 552 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.14
Dann	Benign	0.48

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: rs12001902; hg19: chr9-78715080;