NM_174936.4:c.1503+54_1503+71delGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-55058666-CGTGTGTGTGTGTGTGTGT-C
• rs35115360
• NM_174936.4:c.1503+54_1503+71delGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.1503+54_1503+71delGTGTGTGTGTGTGTGTGT 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 0.063 (417 hom., cov: 0)
  • Exomes 𝑓: 0.037 (109 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.564
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-55058666-CGTGTGTGTGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGTGTGTGTGT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 492235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+54_1503+71delGTGTGTGTGTGTGTGTGT		intron_variant	Intron 9 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1503+20_1503+37delGTGTGTGTGTGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9006 AN: 142358 Hom.: 418 Cov.: 0

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0511

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0544

Gnomad EAS AF: 0.0467

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0442

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.0433

GnomAD2 exomes AF: 0.0361 AC: 5378 AN: 149146 AF XY: 0.0349

Gnomad AFR exome AF: 0.0977

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0543

Gnomad EAS exome AF: 0.0443

Gnomad FIN exome AF: 0.0443

Gnomad NFE exome AF: 0.0308

Gnomad OTH exome AF: 0.0361

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0374 AC: 51399 AN: 1373540 Hom.: 109 AF XY: 0.0369 AC XY: 25129 AN XY: 681136

African (AFR) AF: 0.122 AC: 3819 AN: 31386

American (AMR) AF: 0.0222 AC: 868 AN: 39026

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 1269 AN: 24442

East Asian (EAS) AF: 0.0463 AC: 1670 AN: 36108

South Asian (SAS) AF: 0.0267 AC: 2146 AN: 80428

European-Finnish (FIN) AF: 0.0441 AC: 2080 AN: 47162

Middle Eastern (MID) AF: 0.0398 AC: 155 AN: 3896

European-Non Finnish (NFE) AF: 0.0351 AC: 37045 AN: 1054458

Other (OTH) AF: 0.0414 AC: 2347 AN: 56634

GnomAD4 genome AF: 0.0633 AC: 9020 AN: 142440 Hom.: 417 Cov.: 0 AF XY: 0.0628 AC XY: 4331 AN XY: 69014

African (AFR) AF: 0.130 AC: 4905 AN: 37844

American (AMR) AF: 0.0289 AC: 422 AN: 14600

Ashkenazi Jewish (ASJ) AF: 0.0544 AC: 183 AN: 3364

East Asian (EAS) AF: 0.0460 AC: 218 AN: 4740

South Asian (SAS) AF: 0.0286 AC: 125 AN: 4370

European-Finnish (FIN) AF: 0.0483 AC: 441 AN: 9136

Middle Eastern (MID) AF: 0.0444 AC: 12 AN: 270

European-Non Finnish (NFE) AF: 0.0396 AC: 2585 AN: 65282

Other (OTH) AF: 0.0430 AC: 84 AN: 1954

Alfa AF: 0.0586 Hom.: 1122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Benign:1

Aug 05, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:1

Dec 04, 2017

Color Diagnostics, LLC DBA Color Health

Significance: 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)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35115360; hg19: chr1-55524339;