9-76023881-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP7 BS1_Supporting BS2

The NM_001372043.1(PCSK5):c.555C>T(p.Tyr185=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,609,240 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.014 (200 hom.)
• Consequence: PCSK5 NM_001372043.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.0005907
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.287

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP7: Synonymous conserved (PhyloP=-0.287 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0137 (20017/1457050) while in subpopulation MID AF= 0.0193 (111/5744). AF 95% confidence interval is 0.0164. There are 200 homozygotes in gnomad4_exome. There are 9925 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK5	NM_001372043.1	c.555C>T	p.Tyr185=	splice_region_variant, synonymous_variant	4/38	ENST00000674117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK5	ENST00000674117.1	c.555C>T	p.Tyr185=	splice_region_variant, synonymous_variant	4/38		NM_001372043.1	A2
PCSK5	ENST00000376752.9	c.555C>T	p.Tyr185=	splice_region_variant, synonymous_variant	4/21	1
PCSK5	ENST00000545128.5	c.555C>T	p.Tyr185=	splice_region_variant, synonymous_variant	4/37	5		P4
PCSK5	ENST00000376767.7	n.1067C>T		splice_region_variant, non_coding_transcript_exon_variant	4/14	2

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2137 AN: 152072 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00720

GnomAD3 exomes AF: 0.0131 AC: 3240 AN: 247098 Hom.: 42 AF XY: 0.0130 AC XY: 1734 AN XY: 133502

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00972

Gnomad FIN exome AF: 0.0455

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0137 AC: 20017 AN: 1457050 Hom.: 200 Cov.: 30 AF XY: 0.0137 AC XY: 9925 AN XY: 724628

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00973

Gnomad4 FIN exome AF: 0.0432

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0140 AC: 2136 AN: 152190 Hom.: 22 Cov.: 32 AF XY: 0.0146 AC XY: 1088 AN XY: 74388

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.0437

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.0126 Hom.: 21

Bravo AF: 0.0114

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.00983

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Mar 06, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.80
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00059
dbscSNV1_RF	Benign	0.14
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: rs34417623; hg19: chr9-78638797;