chr9-76197556-G-A

Variant names:

• chr9-76197556-G-A
• rs11144790
• NM_001372043.1:c.2626+7810G>A

Variant summary

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

The NM_001372043.1(PCSK5):​c.2626+7810G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,082 control chromosomes in the GnomAD database, including 1,609 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 0.13 (1609 hom., cov: 33)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.655
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.2626+7810G>A		intron_variant	Intron 20 of 37	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.2626+7810G>A		intron_variant	Intron 20 of 37		NM_001372043.1	ENSP00000500971.1
PCSK5	ENST00000545128.5	c.2626+7810G>A		intron_variant	Intron 20 of 36	5		ENSP00000446280.1
PCSK5	ENST00000424854.6	c.1645+7810G>A		intron_variant	Intron 13 of 30	5		ENSP00000411654.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19561 AN: 151964 Hom.: 1610 Cov.: 33

Gnomad AFR AF: 0.0476

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0775

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.154

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

GnomAD4 genome AF: 0.129 AC: 19561 AN: 152082 Hom.: 1609 Cov.: 33 AF XY: 0.127 AC XY: 9455 AN XY: 74320

African (AFR) AF: 0.0475 AC: 1973 AN: 41494

American (AMR) AF: 0.134 AC: 2050 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 711 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0778 AC: 375 AN: 4820

European-Finnish (FIN) AF: 0.161 AC: 1697 AN: 10542

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12325 AN: 67972

Other (OTH) AF: 0.152 AC: 322 AN: 2112

Alfa AF: 0.155 Hom.: 542

Bravo AF: 0.123

Asia WGS AF: 0.0320 AC: 113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.87
DANN	Benign	0.59
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11144790; hg19: chr9-78812472;