Genetic Variant NM_174936.4:c.799+710G>A (chr1-55053501-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_174936.4(PCSK9):c.799+710G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 152,010 control chromosomes in the GnomAD database, including 27,390 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 27390 hom., cov: 32)

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0720

Publications

11 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.799+710G>A		intron_variant	Intron 5 of 11	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.799+710G>A		intron_variant	Intron 5 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.596

AC:

90480

AN:

151890

Hom.:

27380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.533

Gnomad AMI

AF:

0.651

Gnomad AMR

AF:

0.695

Gnomad ASJ

AF:

0.628

Gnomad EAS

AF:

0.789

Gnomad SAS

AF:

0.592

Gnomad FIN

AF:

0.511

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.606

Gnomad OTH

AF:

0.641

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.596

AC:

90540

AN:

152010

Hom.:

27390

Cov.:

AF XY:

0.595

AC XY:

44191

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.533

AC:

22080

AN:

41446

American (AMR)

AF:

0.695

AC:

10626

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.628

AC:

2180

AN:

3472

East Asian (EAS)

AF:

0.789

AC:

4060

AN:

5146

South Asian (SAS)

AF:

0.592

AC:

2853

AN:

4820

European-Finnish (FIN)

AF:

0.511

AC:

5411

AN:

10580

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.606

AC:

41195

AN:

67946

Other (OTH)

AF:

0.642

AC:

1352

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1878

3756

5633

7511

9389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

758

1516

2274

3032

3790

<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:

0.545

Hom.:

4471

Bravo

AF:

0.609

Asia WGS

AF:

0.688

AC:

2391

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.7

(source)

DANN

Benign

0.41

PhyloP100

0.072

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over