9-76096137-T-G

Variant names:

• chr9-76096137-T-G
• rs1416547
• NM_001372043.1:c.1107+35T>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.1107+35T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,393,828 control chromosomes in the GnomAD database, including 75,126 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 0.29 (6685 hom., cov: 31)
  • Exomes 𝑓: 0.33 (68441 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.913
• Publications: 6 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=-0.77).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372043.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	NM_001372043.1	MANE Select	c.1107+35T>G		intron	N/A	NP_001358972.1
	PCSK5	NM_001190482.2		c.1107+35T>G		intron	N/A	NP_001177411.1
	PCSK5	NM_006200.6		c.1107+35T>G		intron	N/A	NP_006191.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.1107+35T>G		intron	N/A	ENSP00000500971.1
	PCSK5	ENST00000376752.9	TSL:1	c.1107+35T>G		intron	N/A	ENSP00000365943.4
	PCSK5	ENST00000545128.5	TSL:5	c.1107+35T>G		intron	N/A	ENSP00000446280.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44390 AN: 151718 Hom.: 6675 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.305 AC: 71031 AN: 233090 AF XY: 0.309

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.328 AC: 407249 AN: 1241992 Hom.: 68441 Cov.: 17 AF XY: 0.329 AC XY: 206431 AN XY: 627800

African (AFR) AF: 0.254 AC: 7405 AN: 29156

American (AMR) AF: 0.248 AC: 10675 AN: 42968

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 6675 AN: 24572

East Asian (EAS) AF: 0.170 AC: 6532 AN: 38378

South Asian (SAS) AF: 0.362 AC: 29322 AN: 80902

European-Finnish (FIN) AF: 0.297 AC: 15553 AN: 52438

Middle Eastern (MID) AF: 0.208 AC: 1013 AN: 4864

European-Non Finnish (NFE) AF: 0.342 AC: 313273 AN: 915564

Other (OTH) AF: 0.316 AC: 16801 AN: 53150

GnomAD4 genome AF: 0.293 AC: 44434 AN: 151836 Hom.: 6685 Cov.: 31 AF XY: 0.289 AC XY: 21419 AN XY: 74160

African (AFR) AF: 0.258 AC: 10658 AN: 41376

American (AMR) AF: 0.234 AC: 3576 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3464

East Asian (EAS) AF: 0.175 AC: 904 AN: 5162

South Asian (SAS) AF: 0.374 AC: 1791 AN: 4786

European-Finnish (FIN) AF: 0.299 AC: 3142 AN: 10516

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22495 AN: 67944

Other (OTH) AF: 0.275 AC: 580 AN: 2108

Alfa AF: 0.303 Hom.: 1332

Bravo AF: 0.286

Asia WGS AF: 0.319 AC: 1112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.8
DANN	Benign	0.64
PhyloP100		0.91
PromoterAI		-0.0079	Neutral
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: rs1416547; hg19: chr9-78711053; COSMIC: COSV65095079;