rs1278890129

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-55039979-G-A
• chr1-55039979-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_174936.4(PCSK9):​c.142G>A​(p.Glu48Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,580,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E48E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:8
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3833622).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.142G>A	p.Glu48Lys	missense	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.142G>A	p.Glu48Lys	missense	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.142G>A	p.Glu48Lys	missense	Exon 1 of 12	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.142G>A	p.Glu48Lys	missense	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.499G>A	p.Glu167Lys	missense	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.142G>A	p.Glu48Lys	missense	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152272 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000203 AC: 4 AN: 196960 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000420 AC: 6 AN: 1428656 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707592

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: 0.0000492 AC: 4 AN: 81346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50418

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

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096378

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

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152272 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000935 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hypercholesterolemia, autosomal dominant, 3 (3)
-	3	-	not provided (3)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Familial hypercholesterolemia (1)
1	-	-	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.70
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.041
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.037	D
Polyphen		0.0070	B
Vest4		0.69
MutPred		0.40		Gain of ubiquitination at E48 (P = 0.0094)
MVP		0.77
MPC		0.27
ClinPred		0.18	T
GERP RS		-0.17
PromoterAI		0.024	Neutral
Varity_R		0.21
gMVP		0.71
Mutation Taster		=31/69	disease causing

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;