9-76140184-T-G

Variant names:

• chr9-76140184-T-G
• rs1338746
• NM_001372043.1:c.1312+5972T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372043.1(PCSK5):​c.1312+5972T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 151,838 control chromosomes in the GnomAD database, including 20,124 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 0.50 (20124 hom., cov: 32)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.150
• Publications: 3 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 (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.1312+5972T>G		intron_variant	Intron 10 of 37	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.1312+5972T>G		intron_variant	Intron 10 of 37		NM_001372043.1	ENSP00000500971.1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75508 AN: 151724 Hom.: 20092 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.521

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

GnomAD4 genome AF: 0.498 AC: 75588 AN: 151838 Hom.: 20124 Cov.: 32 AF XY: 0.502 AC XY: 37265 AN XY: 74172

African (AFR) AF: 0.574 AC: 23750 AN: 41404

American (AMR) AF: 0.603 AC: 9186 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1474 AN: 3462

East Asian (EAS) AF: 0.942 AC: 4868 AN: 5166

South Asian (SAS) AF: 0.575 AC: 2764 AN: 4810

European-Finnish (FIN) AF: 0.356 AC: 3753 AN: 10532

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28316 AN: 67908

Other (OTH) AF: 0.521 AC: 1101 AN: 2112

Alfa AF: 0.450 Hom.: 31751

Bravo AF: 0.525

Asia WGS AF: 0.727 AC: 2524 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.73
PhyloP100		0.15
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: rs1338746; hg19: chr9-78755100;