Variant 9-76071902-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001372043.1(PCSK5):c.894+4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,612,676 control chromosomes in the GnomAD database, including 25,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2087 hom., cov: 32)

Exomes 𝑓: 0.18 ( 23033 hom. )

Consequence

PCSK5
NM_001372043.1 splice_region, intron

Scores

Splicing: ADA: 0.0001574

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.264

Variant links:

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 links:

PCSK5 (HGNC:):

PCSK5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK5	NM_001372043.1 linkuse as main transcript	c.894+4G>T		splice_region_variant, intron_variant		ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
PCSK5	ENST00000674117.1 linkuse as main transcript	c.894+4G>T	splice_region_variant, intron_variant		NM_001372043.1	ENSP00000500971.1	A0A669KA35
PCSK5	ENST00000376752.9 linkuse as main transcript	c.894+4G>T	splice_region_variant, intron_variant	1		ENSP00000365943.4	Q92824-2
PCSK5	ENST00000545128.5 linkuse as main transcript	c.894+4G>T	splice_region_variant, intron_variant	5		ENSP00000446280.1	Q92824-1
PCSK5	ENST00000376767.7 linkuse as main transcript	n.1406+4G>T	splice_region_variant, intron_variant	2

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24868

AN:

152066

Hom.:

2089

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.229

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.161

GnomAD3 exomes

AF:

0.166

AC:

41159

AN:

248586

Hom.:

3607

AF XY:

0.169

AC XY:

22751

AN XY:

134574

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.0844

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.228

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.191

Gnomad NFE exome

AF:

0.178

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.176

AC:

256535

AN:

1460490

Hom.:

23033

Cov.:

AF XY:

0.177

AC XY:

128315

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.0892

Gnomad4 ASJ exome

AF:

0.150

Gnomad4 EAS exome

AF:

0.233

Gnomad4 SAS exome

AF:

0.174

Gnomad4 FIN exome

AF:

0.189

Gnomad4 NFE exome

AF:

0.179

Gnomad4 OTH exome

AF:

0.172

GnomAD4 genome

AF:

0.163

AC:

24877

AN:

152186

Hom.:

2087

Cov.:

AF XY:

0.164

AC XY:

12219

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.152

Gnomad4 EAS

AF:

0.228

Gnomad4 SAS

AF:

0.166

Gnomad4 FIN

AF:

0.190

Gnomad4 NFE

AF:

0.181

Gnomad4 OTH

AF:

0.158

Alfa

AF:

0.174

Hom.:

3858

Bravo

AF:

0.157

Asia WGS

AF:

0.189

AC:

653

AN:

3478

EpiCase

AF:

0.178

EpiControl

AF:

0.179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.038

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over