chr1-55057688-A-G

Variant names:

• chr1-55057688-A-G
• rs533375
• NM_174936.4:c.1180+174A>G

Variant summary

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

The NM_001407240.1(PCSK9):​c.1303+174A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 152,156 control chromosomes in the GnomAD database, including 51,470 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 0.82 (51470 hom., cov: 32)
• Consequence: PCSK9 NM_001407240.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.703
• Publications: 10 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407240.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1180+174A>G		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1303+174A>G		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.1180+174A>G		intron	N/A	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1180+174A>G		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1537+174A>G		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.1303+174A>G		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124792 AN: 152038 Hom.: 51436 Cov.: 32

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.876

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.845

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.821 AC: 124880 AN: 152156 Hom.: 51470 Cov.: 32 AF XY: 0.823 AC XY: 61187 AN XY: 74386

African (AFR) AF: 0.756 AC: 31345 AN: 41480

American (AMR) AF: 0.876 AC: 13409 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2783 AN: 3470

East Asian (EAS) AF: 0.995 AC: 5152 AN: 5176

South Asian (SAS) AF: 0.888 AC: 4284 AN: 4826

European-Finnish (FIN) AF: 0.822 AC: 8700 AN: 10588

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56395 AN: 67996

Other (OTH) AF: 0.847 AC: 1790 AN: 2114

Alfa AF: 0.822 Hom.: 14015

Bravo AF: 0.821

Asia WGS AF: 0.922 AC: 3206 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.59
PhyloP100		-0.70
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: rs533375; hg19: chr1-55523361;