Genetic Variant PCSK9:c.1503+44_1503+71delGTGTGTGTGTGTGTGTGTGTGTGTGTGT (chr1-55058666-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_174936.4(PCSK9):c.1503+44_1503+71delGTGTGTGTGTGTGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000093 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PCSK9
NM_174936.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.564

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1503+44_1503+71delGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 9 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.1503+20_1503+47delGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00000702

AC:

AN:

142440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000933

AC:

AN:

1392910

Hom.:

AF XY:

0.0000116

AC XY:

AN XY:

690658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31628

American (AMR)

AF:

0.0000253

AC:

AN:

39552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24880

East Asian (EAS)

AF:

0.00

AC:

AN:

36988

South Asian (SAS)

AF:

0.0000246

AC:

AN:

81354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4014

European-Non Finnish (NFE)

AF:

0.00000842

AC:

AN:

1068944

Other (OTH)

AF:

0.0000174

AC:

AN:

57562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000702

AC:

AN:

142440

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68950

show subpopulations

African (AFR)

AF:

0.0000265

AC:

AN:

37766

American (AMR)

AF:

0.00

AC:

AN:

14588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4752

South Asian (SAS)

AF:

0.00

AC:

AN:

4378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65320

Other (OTH)

AF:

0.00

AC:

AN:

1944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1122

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.56

Splicing

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