1-55040059-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001407246.1(PCSK9):c.-513A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,553,126 control chromosomes in the GnomAD database, including 692,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.92 ( 64013 hom., cov: 38)

Exomes 𝑓: 0.95 ( 628779 hom. )

Consequence

PCSK9
NM_001407246.1 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.224

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

hypercholesterolemia, autosomal dominant, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 1-55040059-A-G is Benign according to our data. Variant chr1-55040059-A-G is described in ClinVar as Benign. ClinVar VariationId is 262904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407246.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCSK9	NM_174936.4	MANE Select	c.207+15A>G	intron	N/A	NP_777596.2
PCSK9	NM_001407246.1		c.-513A>G	5_prime_UTR	Exon 1 of 12	NP_001394175.1	A0A669KBG0
PCSK9	NM_001407240.1		c.207+15A>G	intron	N/A	NP_001394169.1	A0AAQ5BGX4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.207+15A>G	intron	N/A	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1		c.564+15A>G	intron	N/A	ENSP00000518176.1	A0AA34QVH0
PCSK9	ENST00000713786.1		c.207+15A>G	intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes

AF:

0.915

AC:

139342

AN:

152240

Hom.:

63976

Cov.:

show subpopulations

Gnomad AFR

AF:

0.835

Gnomad AMI

AF:

0.952

Gnomad AMR

AF:

0.903

Gnomad ASJ

AF:

0.929

Gnomad EAS

AF:

0.943

Gnomad SAS

AF:

0.973

Gnomad FIN

AF:

0.969

Gnomad MID

AF:

0.920

Gnomad NFE

AF:

0.951

Gnomad OTH

AF:

0.921

GnomAD2 exomes

AF:

0.928

AC:

147203

AN:

158652

AF XY:

0.936

show subpopulations

Gnomad AFR exome

AF:

0.830

Gnomad AMR exome

AF:

0.836

Gnomad ASJ exome

AF:

0.928

Gnomad EAS exome

AF:

0.941

Gnomad FIN exome

AF:

0.965

Gnomad NFE exome

AF:

0.951

Gnomad OTH exome

AF:

0.942

GnomAD4 exome

AF:

0.947

AC:

1326590

AN:

1400768

Hom.:

628779

Cov.:

AF XY:

0.949

AC XY:

655717

AN XY:

691306

show subpopulations

African (AFR)

AF:

0.824

AC:

26196

AN:

31786

American (AMR)

AF:

0.844

AC:

30671

AN:

36360

Ashkenazi Jewish (ASJ)

AF:

0.929

AC:

23392

AN:

25188

East Asian (EAS)

AF:

0.957

AC:

34475

AN:

36038

South Asian (SAS)

AF:

0.970

AC:

76973

AN:

79368

European-Finnish (FIN)

AF:

0.965

AC:

47003

AN:

48726

Middle Eastern (MID)

AF:

0.943

AC:

4046

AN:

4292

European-Non Finnish (NFE)

AF:

0.952

AC:

1029220

AN:

1080988

Other (OTH)

AF:

0.941

AC:

54614

AN:

58022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

4455

8911

13366

17822

22277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21248

42496

63744

84992

106240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.915

AC:

139434

AN:

152358

Hom.:

64013

Cov.:

AF XY:

0.917

AC XY:

68323

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.835

AC:

34714

AN:

41572

American (AMR)

AF:

0.902

AC:

13815

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.929

AC:

3224

AN:

3472

East Asian (EAS)

AF:

0.943

AC:

4889

AN:

5182

South Asian (SAS)

AF:

0.973

AC:

4705

AN:

4834

European-Finnish (FIN)

AF:

0.969

AC:

10306

AN:

10632

Middle Eastern (MID)

AF:

0.918

AC:

268

AN:

292

European-Non Finnish (NFE)

AF:

0.951

AC:

64698

AN:

68038

Other (OTH)

AF:

0.921

AC:

1947

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

632

1264

1897

2529

3161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.911

Hom.:

23111

Bravo

AF:

0.904

Asia WGS

AF:

0.953

AC:

3315

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, autosomal dominant, 3 (4)

not specified (4)

Hypercholesterolemia, familial, 1 (3)

Familial hypercholesterolemia (2)

not provided (2)

Hypobetalipoproteinemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.8

(source)

DANN

Benign

0.46

PhyloP100

0.22

PromoterAI

0.12

Neutral

(source)

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over