chr1-55039995-C-T

Position:

chr1-55039995-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

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 the same amino acid substitution has been previously reported as Likely benign in 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:20

Conservation

PhyloP100: 1.52

Variant links:

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]

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
PCSK9	NM_174936.4 link	c.158C>T	p.Ala53Val	missense_variant	1/12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PCSK9	ENST00000302118.5 link	c.158C>T	p.Ala53Val	missense_variant	1/12	1	NM_174936.4	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1 link	c.515C>T	p.Ala172Val	missense_variant	1/12			ENSP00000518176.1
PCSK9	ENST00000673726.1 link	n.158C>T		non_coding_transcript_exon_variant	1/6			ENSP00000501004.1	A0A669KAY4
PCSK9	ENST00000673913.2 link	n.158C>T		non_coding_transcript_exon_variant	1/12			ENSP00000501161.2	A0A669KB81

Frequencies

GnomAD3 genomes

AF:

0.0943

AC:

14354

AN:

152204

Hom.:

823

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.132

AC XY:

93384

AN XY:

705788

show subpopulations

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.:

AF XY:

0.0919

AC XY:

6841

AN XY:

74480

show subpopulations

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:1Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Pathogenic:1Benign:6

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 28, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 01, 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. -
Pathogenic, flagged submission	research	Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -

Hypercholesterolemia, familial, 1

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
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	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not specified

Benign:3

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

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 13, 2024	- -

Familial hypercholesterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 01, 2022	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.095

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.63

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.36

REVEL

Benign

0.065

Sift

Benign

0.31

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.018

MPC

0.22

ClinPred

0.0088

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over