rs28362288

Variant names:

• chr1-55064028-G-C
• rs28362288
• NM_174936.4:c.*444G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-55064028-G-C
• chr1-55064028-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174936.4(PCSK9):​c.*444G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 177,176 control chromosomes in the GnomAD database, including 95 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 0.020 (92 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (3 hom.)
• Consequence: PCSK9 NM_174936.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.126
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.*444G>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.*444G>C		3_prime_UTR_variant	Exon 12 of 12	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2984 AN: 152188 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00314 AC: 78 AN: 24870 Hom.: 3 Cov.: 0 AF XY: 0.00304 AC XY: 38 AN XY: 12514

African (AFR) AF: 0.0477 AC: 45 AN: 944

American (AMR) AF: 0.00570 AC: 12 AN: 2104

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 11 AN: 726

East Asian (EAS) AF: 0.00 AC: 0 AN: 1312

South Asian (SAS) AF: 0.00112 AC: 2 AN: 1790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 962

Middle Eastern (MID) AF: 0.0109 AC: 1 AN: 92

European-Non Finnish (NFE) AF: 0.0000645 AC: 1 AN: 15514

Other (OTH) AF: 0.00421 AC: 6 AN: 1426

GnomAD4 genome AF: 0.0197 AC: 2994 AN: 152306 Hom.: 92 Cov.: 33 AF XY: 0.0190 AC XY: 1416 AN XY: 74482

African (AFR) AF: 0.0675 AC: 2803 AN: 41550

American (AMR) AF: 0.00732 AC: 112 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68020

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0221

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypobetalipoproteinemia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.59
DANN	Benign	0.40
PhyloP100		-0.13
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

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: rs28362288; hg19: chr1-55529701;