1-55053342-G-T

Variant names:

• chr1-55053342-G-T
• rs639750
• NM_174936.4:c.799+551G>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.799+551G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 151,908 control chromosomes in the GnomAD database, including 31,035 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 0.63 (31035 hom., cov: 31)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430
• Publications: 7 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 = 0.772 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.799+551G>T		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.922+551G>T		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.799+551G>T		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.799+551G>T		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1156+551G>T		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.922+551G>T		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96240 AN: 151790 Hom.: 31026 Cov.: 31

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.791

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.677

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

GnomAD4 genome AF: 0.634 AC: 96297 AN: 151908 Hom.: 31035 Cov.: 31 AF XY: 0.631 AC XY: 46819 AN XY: 74232

African (AFR) AF: 0.542 AC: 22446 AN: 41378

American (AMR) AF: 0.723 AC: 11052 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2286 AN: 3470

East Asian (EAS) AF: 0.792 AC: 4086 AN: 5160

South Asian (SAS) AF: 0.583 AC: 2805 AN: 4808

European-Finnish (FIN) AF: 0.557 AC: 5870 AN: 10544

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.670 AC: 45512 AN: 67958

Other (OTH) AF: 0.678 AC: 1430 AN: 2110

Alfa AF: 0.637 Hom.: 9036

Bravo AF: 0.646

Asia WGS AF: 0.685 AC: 2380 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	9.4
DANN	Benign	0.83
PhyloP100		0.043
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: rs639750; hg19: chr1-55519015;