rs1340510

Positions:

• chr9-75961728-G-A
• chr9-75961728-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.298-24404G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 152,020 control chromosomes in the GnomAD database, including 36,618 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 0.69 (36618 hom., cov: 33)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK5	NM_001372043.1	c.298-24404G>A		intron_variant		ENST00000674117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK5	ENST00000674117.1	c.298-24404G>A		intron_variant			NM_001372043.1	A2
PCSK5	ENST00000376752.9	c.298-24404G>A		intron_variant		1
PCSK5	ENST00000545128.5	c.298-24404G>A		intron_variant		5		P4
PCSK5	ENST00000376767.7	n.810-24404G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104635 AN: 151902 Hom.: 36611 Cov.: 33

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.765

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.815

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.666

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.699

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

GnomAD4 genome AF: 0.689 AC: 104675 AN: 152020 Hom.: 36618 Cov.: 33 AF XY: 0.686 AC XY: 51001 AN XY: 74302

Gnomad4 AFR AF: 0.556

Gnomad4 AMR AF: 0.765

Gnomad4 ASJ AF: 0.720

Gnomad4 EAS AF: 0.815

Gnomad4 SAS AF: 0.743

Gnomad4 FIN AF: 0.650

Gnomad4 NFE AF: 0.741

Gnomad4 OTH AF: 0.699

Alfa AF: 0.734 Hom.: 54930

Bravo AF: 0.694

Asia WGS AF: 0.746 AC: 2593 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.67

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: rs1340510; hg19: chr9-78576644;