rs45448095

chr1-55039774-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):c.-64C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,546,470 control chromosomes in the GnomAD database, including 14,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (901 hom., cov: 34)
  • Exomes 𝑓: 0.14 (13741 hom.)
• Consequence: PCSK9 NM_174936.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.546

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-55039774-C-T is Benign according to our data. Variant chr1-55039774-C-T is described in ClinVar as [Benign]. Clinvar id is 36666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55039774-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.-64C>T		5_prime_UTR_variant	1/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.-64C>T		5_prime_UTR_variant	1/12	1	NM_174936.4	P2
PCSK9	ENST00000710286.1	c.294C>T	p.Ala98=	synonymous_variant	1/12			A2
PCSK9	ENST00000673726.1	c.-64C>T		5_prime_UTR_variant, NMD_transcript_variant	1/6
PCSK9	ENST00000673913.2	c.-64C>T		5_prime_UTR_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 14951 AN: 152222 Hom.: 896 Cov.: 34

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.0826

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.137 AC: 190480 AN: 1394130 Hom.: 13741 Cov.: 27 AF XY: 0.137 AC XY: 94782 AN XY: 689374

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.0706

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.0958

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.0981 AC: 14947 AN: 152340 Hom.: 901 Cov.: 34 AF XY: 0.0958 AC XY: 7133 AN XY: 74496

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.0824

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0865

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.108

Alfa AF: 0.108 Hom.: 119

Bravo AF: 0.0972

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

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	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

Hypercholesterolemia, autosomal dominant, 3 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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	8.3
Dann	Benign	0.91

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: rs45448095; hg19: chr1-55505447; COSMIC: COSV56162238;