NM_174936.4:c.800-557G>A

Variant names:

• chr1-55055436-G-A
• rs693668
• NM_174936.4:c.800-557G>A

Variant summary

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

The NM_174936.4(PCSK9):​c.800-557G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 151,924 control chromosomes in the GnomAD database, including 25,593 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 0.56 (25593 hom., cov: 31)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 18 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 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.800-557G>A		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.923-557G>A		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.800-557G>A		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.800-557G>A		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1157-557G>A		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.923-557G>A		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85552 AN: 151806 Hom.: 25591 Cov.: 31

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.563 AC: 85595 AN: 151924 Hom.: 25593 Cov.: 31 AF XY: 0.565 AC XY: 41989 AN XY: 74272

African (AFR) AF: 0.348 AC: 14385 AN: 41380

American (AMR) AF: 0.688 AC: 10510 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2033 AN: 3470

East Asian (EAS) AF: 0.762 AC: 3935 AN: 5164

South Asian (SAS) AF: 0.608 AC: 2926 AN: 4810

European-Finnish (FIN) AF: 0.554 AC: 5845 AN: 10556

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43962 AN: 67944

Other (OTH) AF: 0.602 AC: 1271 AN: 2110

Alfa AF: 0.609 Hom.: 68941

Bravo AF: 0.565

Asia WGS AF: 0.657 AC: 2282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-1.3
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: rs693668; hg19: chr1-55521109;