rs140882057

Variant names:

• chr9-75891316-G-A
• rs140882057
• NM_001372043.1:c.135G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-75891316-G-A
• chr9-75891316-G-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001372043.1(PCSK5):​c.135G>A​(p.Gly45Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,559,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PCSK5 NM_001372043.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-75891316-G-A is Benign according to our data. Variant chr9-75891316-G-A is described in ClinVar as Benign. ClinVar VariationId is 776423.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.

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.135G>A	p.Gly45Gly	synonymous	Exon 1 of 38	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.135G>A	p.Gly45Gly	synonymous	Exon 1 of 37	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.135G>A	p.Gly45Gly	synonymous	Exon 1 of 21	NP_006191.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.135G>A	p.Gly45Gly	synonymous	Exon 1 of 38	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.135G>A	p.Gly45Gly	synonymous	Exon 1 of 21	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.135G>A	p.Gly45Gly	synonymous	Exon 1 of 38	ENSP00000524257.1

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000259 AC: 52 AN: 200614 AF XY: 0.000154

Gnomad AFR exome AF: 0.00422

Gnomad AMR exome AF: 0.0000799

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000107 AC: 150 AN: 1407658 Hom.: 1 Cov.: 32 AF XY: 0.0000758 AC XY: 53 AN XY: 699426

African (AFR) AF: 0.00435 AC: 127 AN: 29212

American (AMR) AF: 0.0000852 AC: 3 AN: 35222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24656

East Asian (EAS) AF: 0.00 AC: 0 AN: 33906

South Asian (SAS) AF: 0.00 AC: 0 AN: 78990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52604

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5622

European-Non Finnish (NFE) AF: 0.00000551 AC: 6 AN: 1089318

Other (OTH) AF: 0.000224 AC: 13 AN: 58128

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74424

African (AFR) AF: 0.00325 AC: 135 AN: 41560

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.00123

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		1.6
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140882057; hg19: chr9-78506232; COSMIC: COSV100950038;