chr1-55039774-C-T

Position:

chr1-55039774-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.546

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 -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	Protein	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.-64C>T		5_prime_UTR_variant	1/12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.-64C>T		5_prime_UTR_variant	1/12	1	NM_174936.4	ENSP00000303208	P2	Q8NBP7-1
PCSK9	ENST00000710286.1 linkuse as main transcript	c.294C>T	p.Ala98=	synonymous_variant	1/12			ENSP00000518176	A2
PCSK9	ENST00000673726.1 linkuse as main transcript	c.-64C>T		5_prime_UTR_variant, NMD_transcript_variant	1/6			ENSP00000501004
PCSK9	ENST00000673913.2 linkuse as main transcript	c.-64C>T		5_prime_UTR_variant, NMD_transcript_variant	1/12			ENSP00000501161

Frequencies

GnomAD3 genomes

AF:

0.0982

AC:

14951

AN:

152222

Hom.:

896

Cov.:

show subpopulations

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.:

AF XY:

0.137

AC XY:

94782

AN XY:

689374

show subpopulations

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.:

AF XY:

0.0958

AC XY:

7133

AN XY:

74496

show subpopulations

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:2

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

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

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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