1-55039551-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_174936.4(PCSK9):c.-287G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00979 in 546,320 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 21 hom., cov: 33)

Exomes 𝑓: 0.0099 ( 44 hom. )

Consequence

PCSK9
NM_174936.4 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.184

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=-0.53).

BP6

Variant 1-55039551-G-A is Benign according to our data. Variant chr1-55039551-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 265911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55039551-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0094 (1432/152350) while in subpopulation AMR AF= 0.0239 (366/15310). AF 95% confidence interval is 0.0219. There are 21 homozygotes in gnomad4. There are 740 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd at 1433 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.-287G>A		5_prime_UTR_variant	1/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.-287G>A		5_prime_UTR_variant	1/12	1	NM_174936.4	P2	Q8NBP7-1
PCSK9	ENST00000710286.1 linkuse as main transcript	c.71G>A	p.Arg24Gln	missense_variant	1/12			A2
PCSK9	ENST00000673726.1 linkuse as main transcript	c.-287G>A		5_prime_UTR_variant, NMD_transcript_variant	1/6
PCSK9	ENST00000673913.2 linkuse as main transcript	c.-287G>A		5_prime_UTR_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes

AF:

0.00941

AC:

1433

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.00800

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00478

GnomAD4 exome

AF:

0.00994

AC:

3916

AN:

393970

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

2062

AN XY:

205878

show subpopulations

Gnomad4 AFR exome

AF:

0.00160

Gnomad4 AMR exome

AF:

0.0201

Gnomad4 ASJ exome

AF:

0.00381

Gnomad4 EAS exome

AF:

0.0000375

Gnomad4 SAS exome

AF:

0.0133

Gnomad4 FIN exome

AF:

0.0108

Gnomad4 NFE exome

AF:

0.0103

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.00940

AC:

1432

AN:

152350

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

740

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00216

Gnomad4 AMR

AF:

0.0239

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0110

Gnomad4 FIN

AF:

0.00800

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00969

Hom.:

Bravo

AF:

0.00859

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hypercholesterolemia, familial, 1

Benign:1

Benign, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

3/450 normocholesterolemic subjects -

Hypobetalipoproteinemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

Cadd

Benign

Dann

Benign

0.95

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