1-55055191-A-G

Variant names:

• chr1-55055191-A-G
• rs557435
• NM_174936.4:c.800-802A>G

Variant summary

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

The NM_174936.4(PCSK9):​c.800-802A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 151,972 control chromosomes in the GnomAD database, including 48,421 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 0.80 (48421 hom., cov: 30)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. 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.800-802A>G		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.923-802A>G		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.800-802A>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.800-802A>G		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1157-802A>G		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.923-802A>G		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120851 AN: 151852 Hom.: 48386 Cov.: 30

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.875

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.890

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.822

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

GnomAD4 genome AF: 0.796 AC: 120948 AN: 151972 Hom.: 48421 Cov.: 30 AF XY: 0.799 AC XY: 59319 AN XY: 74266

African (AFR) AF: 0.712 AC: 29483 AN: 41398

American (AMR) AF: 0.855 AC: 13075 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2646 AN: 3468

East Asian (EAS) AF: 0.949 AC: 4889 AN: 5152

South Asian (SAS) AF: 0.890 AC: 4282 AN: 4810

European-Finnish (FIN) AF: 0.802 AC: 8485 AN: 10582

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.814 AC: 55318 AN: 67958

Other (OTH) AF: 0.824 AC: 1739 AN: 2110

Alfa AF: 0.809 Hom.: 84875

Bravo AF: 0.797

Asia WGS AF: 0.916 AC: 3186 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	6.5
DANN	Benign	0.77
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs557435; hg19: chr1-55520864;