NM_174936.4:c.1503+60_1503+71delGTGTGTGTGTGT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_174936.4(PCSK9):c.1503+60_1503+71delGTGTGTGTGTGT 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. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 787 hom., cov: 0)

Exomes 𝑓: 0.083 ( 626 hom. )

Failed GnomAD Quality Control

Consequence

PCSK9
NM_174936.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

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: Benign. The variant received -16 ACMG points.

BP6

Variant 1-55058666-CGTGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGTGT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 492238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1503+60_1503+71delGTGTGTGTGTGT		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+31delGTGTGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.0970

AC:

13799

AN:

142270

Hom.:

785

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0975

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.0457

Gnomad FIN

AF:

0.0980

Gnomad MID

AF:

0.0608

Gnomad NFE

AF:

0.0942

Gnomad OTH

AF:

0.0747

GnomAD2 exomes

AF:

0.0519

AC:

7738

AN:

149146

AF XY:

0.0477

show subpopulations

Gnomad AFR exome

AF:

0.0658

Gnomad AMR exome

AF:

0.0832

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.0827

Gnomad FIN exome

AF:

0.0550

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0534

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0826

AC:

113841

AN:

1377520

Hom.:

626

AF XY:

0.0803

AC XY:

54873

AN XY:

683266

show subpopulations

African (AFR)

AF:

0.0877

AC:

2754

AN:

31414

American (AMR)

AF:

0.117

AC:

4595

AN:

39276

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

734

AN:

24682

East Asian (EAS)

AF:

0.0902

AC:

3303

AN:

36608

South Asian (SAS)

AF:

0.0436

AC:

3521

AN:

80762

European-Finnish (FIN)

AF:

0.0807

AC:

3846

AN:

47664

Middle Eastern (MID)

AF:

0.0361

AC:

144

AN:

3986

European-Non Finnish (NFE)

AF:

0.0857

AC:

90562

AN:

1056140

Other (OTH)

AF:

0.0769

AC:

4382

AN:

56988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.402

Heterozygous variant carriers

4976

9952

14928

19904

24880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3524

7048

10572

14096

17620

<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:

0.0970

AC:

13812

AN:

142352

Hom.:

787

Cov.:

AF XY:

0.0963

AC XY:

6641

AN XY:

68962

show subpopulations

African (AFR)

AF:

0.0975

AC:

3687

AN:

37824

American (AMR)

AF:

0.137

AC:

1996

AN:

14586

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

102

AN:

3364

East Asian (EAS)

AF:

0.111

AC:

526

AN:

4736

South Asian (SAS)

AF:

0.0446

AC:

195

AN:

4372

European-Finnish (FIN)

AF:

0.0980

AC:

892

AN:

9104

Middle Eastern (MID)

AF:

0.0625

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0942

AC:

6146

AN:

65260

Other (OTH)

AF:

0.0737

AC:

144

AN:

1954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

547

1093

1640

2186

2733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0694

Hom.:

1122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:2

Oct 12, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Benign:1

Aug 05, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.56

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over