9-76291234-A-G

Variant names:

• chr9-76291234-A-G
• rs2842483
• NM_001372043.1:c.3143-999A>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.3143-999A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,146 control chromosomes in the GnomAD database, including 5,452 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 0.26 (5452 hom., cov: 33)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• Publications: 9 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.3143-999A>G		intron_variant	Intron 24 of 37	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.3143-999A>G		intron_variant	Intron 24 of 37		NM_001372043.1	ENSP00000500971.1
PCSK5	ENST00000545128.5	c.3143-999A>G		intron_variant	Intron 24 of 36	5		ENSP00000446280.1
PCSK5	ENST00000424854.6	c.2162-999A>G		intron_variant	Intron 17 of 30	5		ENSP00000411654.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39786 AN: 152028 Hom.: 5441 Cov.: 33

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0809

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.280

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

GnomAD4 genome AF: 0.262 AC: 39824 AN: 152146 Hom.: 5452 Cov.: 33 AF XY: 0.258 AC XY: 19167 AN XY: 74376

African (AFR) AF: 0.334 AC: 13864 AN: 41470

American (AMR) AF: 0.262 AC: 4001 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3470

East Asian (EAS) AF: 0.0814 AC: 423 AN: 5194

South Asian (SAS) AF: 0.187 AC: 900 AN: 4824

European-Finnish (FIN) AF: 0.185 AC: 1954 AN: 10590

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

European-Non Finnish (NFE) AF: 0.251 AC: 17082 AN: 68004

Other (OTH) AF: 0.278 AC: 587 AN: 2114

Alfa AF: 0.256 Hom.: 23287

Bravo AF: 0.274

Asia WGS AF: 0.124 AC: 433 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.8
DANN	Benign	0.63
PhyloP100		0.071
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2842483; hg19: chr9-78906150;