9-76023773-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001372043.1(PCSK5):c.447C>T(p.Asp149=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000888 in 1,613,120 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (4 hom.)
• Consequence: PCSK5 NM_001372043.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0230

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 9-76023773-C-T is Benign according to our data. Variant chr9-76023773-C-T is described in ClinVar as [Benign]. Clinvar id is 786572.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.023 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00491 (747/152284) while in subpopulation AFR AF= 0.017 (707/41564). AF 95% confidence interval is 0.016. There are 5 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK5	NM_001372043.1	c.447C>T	p.Asp149=	synonymous_variant	4/38	ENST00000674117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK5	ENST00000674117.1	c.447C>T	p.Asp149=	synonymous_variant	4/38		NM_001372043.1	A2
PCSK5	ENST00000376752.9	c.447C>T	p.Asp149=	synonymous_variant	4/21	1
PCSK5	ENST00000545128.5	c.447C>T	p.Asp149=	synonymous_variant	4/37	5		P4
PCSK5	ENST00000376767.7	n.959C>T		non_coding_transcript_exon_variant	4/14	2

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 743 AN: 152166 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00116 AC: 292 AN: 250762 Hom.: 3 AF XY: 0.000804 AC XY: 109 AN XY: 135526

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.000785

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000469 AC: 685 AN: 1460836 Hom.: 4 Cov.: 30 AF XY: 0.000391 AC XY: 284 AN XY: 726732

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00491 AC: 747 AN: 152284 Hom.: 5 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74458

Gnomad4 AFR AF: 0.0170

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00264 Hom.: 2

Bravo AF: 0.00581

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 08, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	8.1
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs111544516; hg19: chr9-78638689;