1-55052794-A-G

Position:

• chr1-55052794-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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: Splicing: ADA: 0.001238
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 2.42

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.799+3A>G		splice_region_variant, intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.799+3A>G		splice_region_variant, intron_variant		1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73717 AN: 152018 Hom.: 19687 Cov.: 34

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

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

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

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

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypercholesterolemia, familial, 1 Benign:4

Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 01, 2017	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Jan 12, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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. -

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

Other links and lift over

dbSNP: rs2495477; hg19: chr1-55518467;