9-75891273-G-A

Variant names:

• chr9-75891273-G-A
• rs147273947
• NM_001372043.1:c.92G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001372043.1(PCSK5):​c.92G>A​(p.Arg31Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000793 in 1,529,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: PCSK5 NM_001372043.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020463616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.92G>A	p.Arg31Gln	missense_variant	Exon 1 of 38	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.92G>A	p.Arg31Gln	missense_variant	Exon 1 of 38		NM_001372043.1	ENSP00000500971.1
PCSK5	ENST00000376752.9	c.92G>A	p.Arg31Gln	missense_variant	Exon 1 of 21	1		ENSP00000365943.4
PCSK5	ENST00000545128.5	c.92G>A	p.Arg31Gln	missense_variant	Exon 1 of 37	5		ENSP00000446280.1
PCSK5	ENST00000376767.7	n.604G>A		non_coding_transcript_exon_variant	Exon 1 of 14	2

Frequencies

GnomAD3 genomes AF: 0.000658 AC: 100 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.00100

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000462 AC: 80 AN: 173002 Hom.: 0 AF XY: 0.000447 AC XY: 43 AN XY: 96198

Gnomad AFR exome AF: 0.000471

Gnomad AMR exome AF: 0.000858

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.000547

GnomAD4 exome AF: 0.000809 AC: 1114 AN: 1377824 Hom.: 0 Cov.: 32 AF XY: 0.000776 AC XY: 531 AN XY: 683950

Gnomad4 AFR exome AF: 0.000147

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000960

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74378

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000931 Hom.: 2

Bravo AF: 0.000778

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000461 AC: 56

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92G>A (p.R31Q) alteration is located in exon 1 (coding exon 1) of the PCSK5 gene. This alteration results from a G to A substitution at nucleotide position 92, causing the arginine (R) at amino acid position 31 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;.;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.026, 0.043	.;B;B
Vest4		0.15
MVP		0.53
MPC		2.1
ClinPred		0.050	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.42

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: rs147273947; hg19: chr9-78506189;