rs1165287

Positions:

• chr1-55054539-G-A
• chr1-55054539-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000302118.5(PCSK9):​c.800-1454G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 152,034 control chromosomes in the GnomAD database, including 23,458 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 0.53 (23458 hom., cov: 32)
• Consequence: PCSK9 ENST00000302118.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.585

Genes affected

PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) 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 autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.800-1454G>A		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.800-1454G>A		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79834 AN: 151916 Hom.: 23458 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.573

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

GnomAD4 genome AF: 0.525 AC: 79855 AN: 152034 Hom.: 23458 Cov.: 32 AF XY: 0.528 AC XY: 39218 AN XY: 74306

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.676

Gnomad4 ASJ AF: 0.578

Gnomad4 EAS AF: 0.758

Gnomad4 SAS AF: 0.583

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.574

Alfa AF: 0.546 Hom.: 3252

Bravo AF: 0.525

Asia WGS AF: 0.630 AC: 2190 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.0
DANN	Benign	0.53

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: rs1165287; hg19: chr1-55520212;