1-55059727-G-A

Variant names:

• chr1-55059727-G-A
• rs483462
• NM_174936.4:c.1681+64G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.1681+64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,526,076 control chromosomes in the GnomAD database, including 374,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32361 hom., cov: 34)
  • Exomes 𝑓: 0.70 (341704 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 1-55059727-G-A is Benign according to our data. Variant chr1-55059727-G-A is described in ClinVar as Benign. ClinVar VariationId is 265948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1681+64G>A		intron_variant	Intron 10 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1681+64G>A		intron_variant	Intron 10 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96354 AN: 152022 Hom.: 32358 Cov.: 34

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.681

GnomAD4 exome AF: 0.702 AC: 965006 AN: 1373936 Hom.: 341704 AF XY: 0.705 AC XY: 476105 AN XY: 675774

African (AFR) AF: 0.380 AC: 11797 AN: 31060

American (AMR) AF: 0.828 AC: 29192 AN: 35254

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 15327 AN: 24514

East Asian (EAS) AF: 0.860 AC: 30416 AN: 35358

South Asian (SAS) AF: 0.753 AC: 58653 AN: 77890

European-Finnish (FIN) AF: 0.721 AC: 34407 AN: 47720

Middle Eastern (MID) AF: 0.703 AC: 2819 AN: 4012

European-Non Finnish (NFE) AF: 0.700 AC: 743160 AN: 1061214

Other (OTH) AF: 0.689 AC: 39235 AN: 56914

GnomAD4 genome AF: 0.633 AC: 96377 AN: 152140 Hom.: 32361 Cov.: 34 AF XY: 0.641 AC XY: 47648 AN XY: 74376

African (AFR) AF: 0.400 AC: 16572 AN: 41478

American (AMR) AF: 0.776 AC: 11861 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2177 AN: 3468

East Asian (EAS) AF: 0.859 AC: 4437 AN: 5166

South Asian (SAS) AF: 0.765 AC: 3700 AN: 4834

European-Finnish (FIN) AF: 0.719 AC: 7611 AN: 10588

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47741 AN: 67996

Other (OTH) AF: 0.683 AC: 1444 AN: 2114

Alfa AF: 0.674 Hom.: 22008

Bravo AF: 0.627

Asia WGS AF: 0.771 AC: 2679 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0050
DANN	Benign	0.45
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs483462; hg19: chr1-55525400;