rs28385701

Positions:

• chr1-55039978-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_174936.4(PCSK9):​c.141C>T​(p.Ser47=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 1,580,712 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0083 (8 hom., cov: 34)
  • Exomes 𝑓: 0.0093 (100 hom.)
• Consequence: PCSK9 NM_174936.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: -1.90

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-55039978-C-T is Benign according to our data. Variant chr1-55039978-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262902.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=11, Uncertain_significance=2}. Variant chr1-55039978-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00833 (1270/152386) while in subpopulation SAS AF= 0.0134 (65/4834). AF 95% confidence interval is 0.0108. There are 8 homozygotes in gnomad4. There are 658 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1270 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.141C>T	p.Ser47=	synonymous_variant	1/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.141C>T	p.Ser47=	synonymous_variant	1/12	1	NM_174936.4	P2
PCSK9	ENST00000710286.1	c.498C>T	p.Ser166=	synonymous_variant	1/12			A2
PCSK9	ENST00000673913.2	c.141C>T	p.Ser47=	synonymous_variant, NMD_transcript_variant	1/12
PCSK9	ENST00000673726.1	c.141C>T	p.Ser47=	synonymous_variant, NMD_transcript_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1271 AN: 152268 Hom.: 8 Cov.: 34

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0100 AC: 1973 AN: 196516 Hom.: 14 AF XY: 0.0102 AC XY: 1082 AN XY: 105660

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.0000675

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00927 AC: 13238 AN: 1428326 Hom.: 100 Cov.: 31 AF XY: 0.00947 AC XY: 6697 AN XY: 707412

Gnomad4 AFR exome AF: 0.00165

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.0000528

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00896

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00833 AC: 1270 AN: 152386 Hom.: 8 Cov.: 34 AF XY: 0.00883 AC XY: 658 AN XY: 74520

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0134

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0111 Hom.: 10

Bravo AF: 0.00818

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 02, 2017	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -

Hypercholesterolemia, autosomal dominant, 3 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	May 31, 2017	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PCSK9: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -

Hypobetalipoproteinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2015

This alteration is classified as likely 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, criteria provided, single submitter

clinical testing

GENinCode PLC

Jul 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.1
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs28385701; hg19: chr1-55505651;