rs1258095

Variant names:

• chr9-76055477-G-A
• rs1258095
• NM_001372043.1:c.633-12478G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372043.1(PCSK5):​c.633-12478G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 151,254 control chromosomes in the GnomAD database, including 3,967 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 0.20 (3967 hom., cov: 32)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.120
• Publications: 2 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.633-12478G>A		intron_variant	Intron 5 of 37	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.633-12478G>A		intron_variant	Intron 5 of 37		NM_001372043.1	ENSP00000500971.1
PCSK5	ENST00000376752.9	c.633-12478G>A		intron_variant	Intron 5 of 20	1		ENSP00000365943.4
PCSK5	ENST00000545128.5	c.633-12478G>A		intron_variant	Intron 5 of 36	5		ENSP00000446280.1
PCSK5	ENST00000376767.7	n.1145-12478G>A		intron_variant	Intron 5 of 13	2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30472 AN: 151140 Hom.: 3966 Cov.: 32

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.00175

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.353

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.219

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

GnomAD4 genome AF: 0.202 AC: 30480 AN: 151254 Hom.: 3967 Cov.: 32 AF XY: 0.203 AC XY: 14968 AN XY: 73828

African (AFR) AF: 0.0540 AC: 2225 AN: 41202

American (AMR) AF: 0.199 AC: 3019 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1008 AN: 3464

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5142

South Asian (SAS) AF: 0.148 AC: 703 AN: 4754

European-Finnish (FIN) AF: 0.317 AC: 3301 AN: 10416

Middle Eastern (MID) AF: 0.366 AC: 106 AN: 290

European-Non Finnish (NFE) AF: 0.286 AC: 19382 AN: 67766

Other (OTH) AF: 0.221 AC: 465 AN: 2106

Alfa AF: 0.267 Hom.: 3695

Bravo AF: 0.186

Asia WGS AF: 0.0620 AC: 218 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	9.0
DANN	Benign	0.66
PhyloP100		0.12
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: rs1258095; hg19: chr9-78670393; COSMIC: COSV65092567;