1-55039551-G-T

Variant names:

• chr1-55039551-G-T
• rs72658888
• NM_174936.4:c.-287G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_174936.4(PCSK9):​c.-287G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000508 in 393,996 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: PCSK9 NM_174936.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.184
• Publications: 6 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).

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.-287G>T		5_prime_UTR	Exon 1 of 12	NP_777596.2
	PCSK9	NR_110451.3		n.4G>T		non_coding_transcript_exon	Exon 1 of 10
	PCSK9	NR_176318.1		n.4G>T		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.-287G>T		5_prime_UTR	Exon 1 of 12	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.71G>T	p.Arg24Leu	missense	Exon 1 of 12	ENSP00000518176.1
	PCSK9	ENST00000673726.2		n.-287G>T		non_coding_transcript_exon	Exon 1 of 13	ENSP00000501004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000508 AC: 2 AN: 393996 Hom.: 0 Cov.: 2 AF XY: 0.00000486 AC XY: 1 AN XY: 205896

African (AFR) AF: 0.00 AC: 0 AN: 10644

American (AMR) AF: 0.00 AC: 0 AN: 16268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12068

East Asian (EAS) AF: 0.00 AC: 0 AN: 26696

South Asian (SAS) AF: 0.0000488 AC: 2 AN: 40988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 236826

Other (OTH) AF: 0.00 AC: 0 AN: 23058

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.4
DANN	Benign	0.94
PhyloP100		0.18
PromoterAI		0.054	Neutral
Mutation Taster		=300/0	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: rs72658888; hg19: chr1-55505224;