rs562556

chr1-55058564-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):c.1420G>A(p.Val474Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,611,942 control chromosomes in the GnomAD database, including 560,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. V474V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.83 (52804 hom., cov: 31)
  • Exomes 𝑓: 0.83 (507651 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.619

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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_174936.4
• BP4: Computational evidence support a benign effect (MetaRNN=7.670029E-7).
• BP6: Variant 1-55058564-G-A is Benign according to our data. Variant chr1-55058564-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 201124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058564-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.1420G>A	p.Val474Ile	missense_variant	9/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.1420G>A	p.Val474Ile	missense_variant	9/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.832 AC: 126474 AN: 152014 Hom.: 52772 Cov.: 31

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.856

GnomAD3 exomes AF: 0.857 AC: 215212 AN: 251218 Hom.: 92504 AF XY: 0.854 AC XY: 116038 AN XY: 135850

Gnomad AFR exome AF: 0.787

Gnomad AMR exome AF: 0.915

Gnomad ASJ exome AF: 0.814

Gnomad EAS exome AF: 0.993

Gnomad SAS exome AF: 0.874

Gnomad FIN exome AF: 0.826

Gnomad NFE exome AF: 0.832

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.833 AC: 1216353 AN: 1459810 Hom.: 507651 Cov.: 86 AF XY: 0.834 AC XY: 605946 AN XY: 726216

Gnomad4 AFR exome AF: 0.790

Gnomad4 AMR exome AF: 0.911

Gnomad4 ASJ exome AF: 0.813

Gnomad4 EAS exome AF: 0.978

Gnomad4 SAS exome AF: 0.874

Gnomad4 FIN exome AF: 0.829

Gnomad4 NFE exome AF: 0.824

Gnomad4 OTH exome AF: 0.836

GnomAD4 genome AF: 0.832 AC: 126561 AN: 152132 Hom.: 52804 Cov.: 31 AF XY: 0.834 AC XY: 61987 AN XY: 74358

Gnomad4 AFR AF: 0.789

Gnomad4 AMR AF: 0.883

Gnomad4 ASJ AF: 0.815

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.887

Gnomad4 FIN AF: 0.822

Gnomad4 NFE AF: 0.831

Gnomad4 OTH AF: 0.858

Alfa AF: 0.832 Hom.: 111826

Bravo AF: 0.834

TwinsUK AF: 0.821 AC: 3045

ALSPAC AF: 0.807 AC: 3110

ESP6500AA AF: 0.787 AC: 3468

ESP6500EA AF: 0.833 AC: 7168

ExAC AF: 0.854 AC: 103723

Asia WGS AF: 0.923 AC: 3208 AN: 3476

EpiCase AF: 0.829

EpiControl AF: 0.825

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Hypercholesterolemia, familial, 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	MAF = 20% in 100 subjects with average plasma cholesterol -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypobetalipoproteinemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Feb 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.036
Dann	Benign	0.83
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.051
Sift	Benign	0.41	T
Sift4G	Benign	0.19	T
Polyphen		0.013	B
Vest4		0.025
MPC		0.18
ClinPred		0.015	T
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.049
gMVP		0.51

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: rs562556; hg19: chr1-55524237; COSMIC: COSV56163657;