NM_001372043.1:c.633-17095T>G

Variant names:

• chr9-76050860-T-G
• rs7047865
• NM_001372043.1:c.633-17095T>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.633-17095T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 151,852 control chromosomes in the GnomAD database, including 20,411 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 (20411 hom., cov: 31)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.633-17095T>G		intron_variant	Intron 5 of 37	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.633-17095T>G		intron_variant	Intron 5 of 37		NM_001372043.1	ENSP00000500971.1
PCSK5	ENST00000376752.9	c.633-17095T>G		intron_variant	Intron 5 of 20	1		ENSP00000365943.4
PCSK5	ENST00000545128.5	c.633-17095T>G		intron_variant	Intron 5 of 36	5		ENSP00000446280.1
PCSK5	ENST00000376767.7	n.1145-17095T>G		intron_variant	Intron 5 of 13	2

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75659 AN: 151734 Hom.: 20356 Cov.: 31

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.472

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

GnomAD4 genome AF: 0.499 AC: 75769 AN: 151852 Hom.: 20411 Cov.: 31 AF XY: 0.499 AC XY: 36992 AN XY: 74200

African (AFR) AF: 0.704 AC: 29164 AN: 41446

American (AMR) AF: 0.450 AC: 6860 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1457 AN: 3472

East Asian (EAS) AF: 0.632 AC: 3258 AN: 5152

South Asian (SAS) AF: 0.641 AC: 3071 AN: 4792

European-Finnish (FIN) AF: 0.323 AC: 3406 AN: 10536

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 27040 AN: 67910

Other (OTH) AF: 0.475 AC: 997 AN: 2098

Alfa AF: 0.446 Hom.: 32893

Bravo AF: 0.513

Asia WGS AF: 0.624 AC: 2171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.62
DANN	Benign	0.58
PhyloP100		-0.49
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: rs7047865; hg19: chr9-78665776;