chr9-76096137-T-G

Position:

• chr9-76096137-T-G

Variant summary

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

The NM_001372043.1(PCSK5):​c.1107+35T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,393,828 control chromosomes in the GnomAD database, including 75,126 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 0.29 (6685 hom., cov: 31)
  • Exomes 𝑓: 0.33 (68441 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.913

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]

PCSK5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.1107+35T>G		intron_variant		ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.1107+35T>G		intron_variant			NM_001372043.1	ENSP00000500971.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44390 AN: 151718 Hom.: 6675 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.270

GnomAD3 exomes AF: 0.305 AC: 71031 AN: 233090 Hom.: 10968 AF XY: 0.309 AC XY: 38888 AN XY: 125768

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.186

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.328 AC: 407249 AN: 1241992 Hom.: 68441 Cov.: 17 AF XY: 0.329 AC XY: 206431 AN XY: 627800

Gnomad4 AFR exome AF: 0.254

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.362

Gnomad4 FIN exome AF: 0.297

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.316

GnomAD4 genome AF: 0.293 AC: 44434 AN: 151836 Hom.: 6685 Cov.: 31 AF XY: 0.289 AC XY: 21419 AN XY: 74160

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.374

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.275

Alfa AF: 0.303 Hom.: 1332

Bravo AF: 0.286

Asia WGS AF: 0.319 AC: 1112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.8
DANN	Benign	0.64

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: rs1416547; hg19: chr9-78711053; COSMIC: COSV65095079;