1-55039593-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_174936.4(PCSK9):c.-245G>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 0.00824 in 598,260 control chromosomes in the GnomAD database, including 181 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 0.024 ( 136 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 45 hom. )

Consequence

PCSK9
NM_174936.4 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.0100

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 1-55039593-G-T is Benign according to our data. Variant chr1-55039593-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265912.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.-245G>T		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.-245G>T		5_prime_UTR_variant	1/12	1	NM_174936.4	P2	Q8NBP7-1
PCSK9	ENST00000710286.1 linkuse as main transcript	c.113G>T	p.Ser38Ile	missense_variant	1/12			A2
PCSK9	ENST00000673726.1 linkuse as main transcript	c.-245G>T		5_prime_UTR_variant, NMD_transcript_variant	1/6
PCSK9	ENST00000673913.2 linkuse as main transcript	c.-245G>T		5_prime_UTR_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes

AF:

0.0237

AC:

3601

AN:

152212

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0833

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0143

GnomAD4 exome

AF:

0.00293

AC:

1308

AN:

445930

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

566

AN XY:

233990

show subpopulations

Gnomad4 AFR exome

AF:

0.0836

Gnomad4 AMR exome

AF:

0.00527

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000177

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000214

Gnomad4 OTH exome

AF:

0.00563

GnomAD4 genome

AF:

0.0238

AC:

3621

AN:

152330

Hom.:

136

Cov.:

AF XY:

0.0222

AC XY:

1653

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0835

Gnomad4 AMR

AF:

0.00653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00912

Hom.:

Bravo

AF:

0.0264

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1

Uncertain significance, 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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

Cadd

Benign

7.3

Dann

Benign

0.87

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