rs11144688

Variant names:

• chr9-75927370-G-A
• rs11144688
• NM_001372043.1:c.193-5009G>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.193-5009G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 152,150 control chromosomes in the GnomAD database, including 851 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 0.092 (851 hom., cov: 32)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.350
• Publications: 49 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.193-5009G>A		intron_variant	Intron 1 of 37	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.193-5009G>A		intron_variant	Intron 1 of 37		NM_001372043.1	ENSP00000500971.1
PCSK5	ENST00000376752.9	c.193-5009G>A		intron_variant	Intron 1 of 20	1		ENSP00000365943.4
PCSK5	ENST00000545128.5	c.193-5009G>A		intron_variant	Intron 1 of 36	5		ENSP00000446280.1
PCSK5	ENST00000376767.7	n.705-5009G>A		intron_variant	Intron 1 of 13	2

Frequencies

GnomAD3 genomes AF: 0.0924 AC: 14044 AN: 152032 Hom.: 851 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.0923 AC: 14036 AN: 152150 Hom.: 851 Cov.: 32 AF XY: 0.0940 AC XY: 6993 AN XY: 74372

African (AFR) AF: 0.0234 AC: 971 AN: 41538

American (AMR) AF: 0.113 AC: 1728 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3470

East Asian (EAS) AF: 0.0504 AC: 261 AN: 5174

South Asian (SAS) AF: 0.0717 AC: 345 AN: 4810

European-Finnish (FIN) AF: 0.153 AC: 1621 AN: 10566

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8312 AN: 68004

Other (OTH) AF: 0.104 AC: 219 AN: 2106

Alfa AF: 0.114 Hom.: 3558

Bravo AF: 0.0855

Asia WGS AF: 0.0710 AC: 248 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.59
PhyloP100		0.35
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: rs11144688; hg19: chr9-78542286;