1-55040059-A-T

Variant names:

• chr1-55040059-A-T
• rs2495482
• NM_174936.4:c.207+15A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001407246.1(PCSK9):​c.-513A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 38)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 NM_001407246.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.224
• Publications: 14 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-55040059-A-T is Benign according to our data. Variant chr1-55040059-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2829837.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407246.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.207+15A>T		intron	N/A	NP_777596.2
	PCSK9	NM_001407246.1		c.-513A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001394175.1	A0A669KBG0
	PCSK9	NM_001407246.1		c.-513A>T		5_prime_UTR	Exon 1 of 12	NP_001394175.1	A0A669KBG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.207+15A>T		intron	N/A	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.564+15A>T		intron	N/A	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.207+15A>T		intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes Cov.: 38

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1400786 Hom.: 0 Cov.: 65 AF XY: 0.00 AC XY: 0 AN XY: 691314

African (AFR) AF: 0.00 AC: 0 AN: 31786

American (AMR) AF: 0.00 AC: 0 AN: 36366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 36038

South Asian (SAS) AF: 0.00 AC: 0 AN: 79370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080996

Other (OTH) AF: 0.00 AC: 0 AN: 58022

GnomAD4 genome Cov.: 38

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, autosomal dominant, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.4
DANN	Benign	0.56
PhyloP100		0.22
PromoterAI		0.091	Neutral

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: rs2495482; hg19: chr1-55505732;