chr9-76092035-T-G

Variant names:

• chr9-76092035-T-G
• rs1029035
• NM_001372043.1:c.895-3855T>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.895-3855T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 151,732 control chromosomes in the GnomAD database, including 17,185 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 0.47 (17185 hom., cov: 30)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0440
• Publications: 6 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]

PCSK5 Gene-Disease associations (from GenCC):

• syndromic congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372043.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	NM_001372043.1	MANE Select	c.895-3855T>G		intron	N/A	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.895-3855T>G		intron	N/A	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.895-3855T>G		intron	N/A	NP_006191.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.895-3855T>G		intron	N/A	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.895-3855T>G		intron	N/A	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.895-3855T>G		intron	N/A	ENSP00000524257.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71553 AN: 151612 Hom.: 17173 Cov.: 30

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.423

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

GnomAD4 genome AF: 0.472 AC: 71604 AN: 151732 Hom.: 17185 Cov.: 30 AF XY: 0.468 AC XY: 34683 AN XY: 74138

African (AFR) AF: 0.502 AC: 20734 AN: 41340

American (AMR) AF: 0.360 AC: 5500 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1407 AN: 3472

East Asian (EAS) AF: 0.348 AC: 1785 AN: 5128

South Asian (SAS) AF: 0.533 AC: 2555 AN: 4792

European-Finnish (FIN) AF: 0.461 AC: 4855 AN: 10538

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.492 AC: 33396 AN: 67880

Other (OTH) AF: 0.420 AC: 885 AN: 2108

Alfa AF: 0.485 Hom.: 10350

Bravo AF: 0.464

Asia WGS AF: 0.467 AC: 1621 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.42
PhyloP100		-0.044
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: rs1029035; hg19: chr9-78706951;