1-55039995-C-T

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.158C>T(p.Ala53Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,578,058 control chromosomes in the GnomAD database, including 13,709 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 Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.094 (828 hom., cov: 34)
  • Exomes 𝑓: 0.13 (12881 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:18
• Conservation: PhyloP100: 1.52

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_174936.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0010536611).
• BP6: Variant 1-55039995-C-T is Benign according to our data. Variant chr1-55039995-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55039995-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.158C>T	p.Ala53Val	missense_variant	1/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.158C>T	p.Ala53Val	missense_variant	1/12	1	NM_174936.4	P2
PCSK9	ENST00000710286.1	c.515C>T	p.Ala172Val	missense_variant	1/12			A2
PCSK9	ENST00000673913.2	c.158C>T	p.Ala53Val	missense_variant, NMD_transcript_variant	1/12
PCSK9	ENST00000673726.1	c.158C>T	p.Ala53Val	missense_variant, NMD_transcript_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.0943 AC: 14354 AN: 152204 Hom.: 823 Cov.: 34

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.0752

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.0999

GnomAD3 exomes AF: 0.114 AC: 21927 AN: 192322 Hom.: 1361 AF XY: 0.119 AC XY: 12258 AN XY: 103386

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.0604

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.122

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.0908

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.131 AC: 187059 AN: 1425738 Hom.: 12881 Cov.: 31 AF XY: 0.132 AC XY: 93384 AN XY: 705788

Gnomad4 AFR exome AF: 0.0190

Gnomad4 AMR exome AF: 0.0643

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.0949

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.0942 AC: 14351 AN: 152320 Hom.: 828 Cov.: 34 AF XY: 0.0919 AC XY: 6841 AN XY: 74480

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.0750

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0863

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.101

Alfa AF: 0.120 Hom.: 1429

Bravo AF: 0.0929

TwinsUK AF: 0.124 AC: 461

ALSPAC AF: 0.143 AC: 553

ESP6500AA AF: 0.0288 AC: 126

ESP6500EA AF: 0.130 AC: 1111

ExAC AF: 0.0935 AC: 11112

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Pathogenic:1 Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 28, 2021	- -
Pathogenic, flagged submission	research	Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	-	- -

Hypercholesterolemia, familial, 1 Benign:5

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 = 7% in 100 subjects with average plasma cholesterol -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypobetalipoproteinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 16, 2018

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as 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 14, 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	0.085
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.065
Sift	Benign	0.31	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.22
ClinPred		0.0088	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.72

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: rs11583680; hg19: chr1-55505668; COSMIC: COSV100134955;