NM_174936.4:c.142G>T

Variant names:

• chr1-55039979-G-T
• rs1278890129
• NM_174936.4:c.142G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 10P and 2B. PVS1 PM2 BP6_Moderate

The NM_174936.4(PCSK9):​c.142G>T​(p.Glu48*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. E48E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PCSK9 NM_174936.4 stop_gained
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.704
• Publications: 2 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_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-55039979-G-T is Benign according to our data. Variant chr1-55039979-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 927517.Status of the report is criteria_provided_single_submitter, 1 stars.

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.142G>T	p.Glu48*	stop_gained	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.142G>T	p.Glu48*	stop_gained	Exon 1 of 13	NP_001394169.1
	PCSK9	NM_001407241.1		c.142G>T	p.Glu48*	stop_gained	Exon 1 of 12	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.142G>T	p.Glu48*	stop_gained	Exon 1 of 12	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.499G>T	p.Glu167*	stop_gained	Exon 1 of 12	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.142G>T	p.Glu48*	stop_gained	Exon 1 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428660 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707594

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32798

American (AMR) AF: 0.00 AC: 0 AN: 40396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25486

East Asian (EAS) AF: 0.00 AC: 0 AN: 37904

South Asian (SAS) AF: 0.00 AC: 0 AN: 81346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4798

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096380

Other (OTH) AF: 0.00 AC: 0 AN: 59132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Benign:1

Sep 30, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.61	D
PhyloP100		0.70
Vest4		0.52
GERP RS		-0.17
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=14/186	disease causing (fs/PTC)

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: rs1278890129; hg19: chr1-55505652;