1-55052794-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_174936.4(PCSK9):​c.799+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,612,790 control chromosomes in the GnomAD database, including 144,840 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 19713 hom., cov: 34)
Exomes 𝑓: 0.41 ( 125127 hom. )

Consequence

PCSK9
NM_174936.4 splice_region, intron

Scores

2
Splicing: ADA: 0.001238
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
Variant 1-55052794-A-G is Benign according to our data. Variant chr1-55052794-A-G is described in ClinVar as [Benign]. Clinvar id is 262908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55052794-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCSK9NM_174936.4 linkc.799+3A>G splice_region_variant, intron_variant Intron 5 of 11 ENST00000302118.5 NP_777596.2 Q8NBP7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCSK9ENST00000302118.5 linkc.799+3A>G splice_region_variant, intron_variant Intron 5 of 11 1 NM_174936.4 ENSP00000303208.5 Q8NBP7-1

Frequencies

GnomAD3 genomes
AF:
0.485
AC:
73717
AN:
152018
Hom.:
19687
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.716
Gnomad AMI
AF:
0.392
Gnomad AMR
AF:
0.347
Gnomad ASJ
AF:
0.464
Gnomad EAS
AF:
0.259
Gnomad SAS
AF:
0.486
Gnomad FIN
AF:
0.450
Gnomad MID
AF:
0.522
Gnomad NFE
AF:
0.401
Gnomad OTH
AF:
0.446
GnomAD3 exomes
AF:
0.419
AC:
103408
AN:
247090
Hom.:
23053
AF XY:
0.421
AC XY:
56506
AN XY:
134328
show subpopulations
Gnomad AFR exome
AF:
0.724
Gnomad AMR exome
AF:
0.302
Gnomad ASJ exome
AF:
0.469
Gnomad EAS exome
AF:
0.255
Gnomad SAS exome
AF:
0.495
Gnomad FIN exome
AF:
0.450
Gnomad NFE exome
AF:
0.407
Gnomad OTH exome
AF:
0.404
GnomAD4 exome
AF:
0.409
AC:
596883
AN:
1460654
Hom.:
125127
Cov.:
76
AF XY:
0.411
AC XY:
298621
AN XY:
726638
show subpopulations
Gnomad4 AFR exome
AF:
0.725
Gnomad4 AMR exome
AF:
0.307
Gnomad4 ASJ exome
AF:
0.468
Gnomad4 EAS exome
AF:
0.268
Gnomad4 SAS exome
AF:
0.491
Gnomad4 FIN exome
AF:
0.444
Gnomad4 NFE exome
AF:
0.398
Gnomad4 OTH exome
AF:
0.421
GnomAD4 genome
AF:
0.485
AC:
73797
AN:
152136
Hom.:
19713
Cov.:
34
AF XY:
0.482
AC XY:
35881
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.716
Gnomad4 AMR
AF:
0.347
Gnomad4 ASJ
AF:
0.464
Gnomad4 EAS
AF:
0.259
Gnomad4 SAS
AF:
0.486
Gnomad4 FIN
AF:
0.450
Gnomad4 NFE
AF:
0.401
Gnomad4 OTH
AF:
0.445
Alfa
AF:
0.424
Hom.:
18908
Bravo
AF:
0.484
Asia WGS
AF:
0.387
AC:
1348
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:4
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 11, 2023
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Benign:4
Jun 01, 2017
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2016
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

-
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Mar 01, 2016
Iberoamerican FH Network
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

not specified Benign:3
Sep 28, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:2
Jul 01, 2022
GENinCode PLC
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 09, 2023
Cohesion Phenomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hypobetalipoproteinemia Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Cardiovascular phenotype Benign:1
Dec 08, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
BayesDel_noAF
Benign
-0.40
CADD
Benign
16
DANN
Benign
0.91
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0012
dbscSNV1_RF
Benign
0.014
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.

Other links and lift over

dbSNP: rs2495477; hg19: chr1-55518467; API