1-55039974-G-T

Variant names:

• chr1-55039974-G-T
• rs11591147
• NM_174936.4:c.137G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_174936.4(PCSK9):​c.137G>T​(p.Arg46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,580,590 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 34)
  • Exomes 𝑓: 0.015 (209 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:17 O:1
• Conservation: PhyloP100: -0.775
• Publications: 472 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019936264).
• BP6: Variant 1-55039974-G-T is Benign according to our data. Variant chr1-55039974-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1866/152404) while in subpopulation NFE AF = 0.0162 (1104/68046). AF 95% confidence interval is 0.0154. There are 17 homozygotes in GnomAd4. There are 1002 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

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.137G>T	p.Arg46Leu	missense	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.137G>T	p.Arg46Leu	missense	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.137G>T	p.Arg46Leu	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.137G>T	p.Arg46Leu	missense	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.494G>T	p.Arg165Leu	missense	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.137G>T	p.Arg46Leu	missense	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1866 AN: 152286 Hom.: 17 Cov.: 34

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0119 AC: 2341 AN: 196220 AF XY: 0.0119

Gnomad AFR exome AF: 0.00242

Gnomad AMR exome AF: 0.00644

Gnomad ASJ exome AF: 0.00464

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0417

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.0151 AC: 21634 AN: 1428186 Hom.: 209 Cov.: 31 AF XY: 0.0145 AC XY: 10261 AN XY: 707338

African (AFR) AF: 0.00229 AC: 75 AN: 32800

American (AMR) AF: 0.00679 AC: 273 AN: 40196

Ashkenazi Jewish (ASJ) AF: 0.00514 AC: 131 AN: 25476

East Asian (EAS) AF: 0.00 AC: 0 AN: 37878

South Asian (SAS) AF: 0.00108 AC: 88 AN: 81336

European-Finnish (FIN) AF: 0.0382 AC: 1927 AN: 50394

Middle Eastern (MID) AF: 0.00537 AC: 26 AN: 4844

European-Non Finnish (NFE) AF: 0.0167 AC: 18328 AN: 1096136

Other (OTH) AF: 0.0133 AC: 786 AN: 59126

GnomAD4 genome AF: 0.0122 AC: 1866 AN: 152404 Hom.: 17 Cov.: 34 AF XY: 0.0134 AC XY: 1002 AN XY: 74526

African (AFR) AF: 0.00262 AC: 109 AN: 41602

American (AMR) AF: 0.00869 AC: 133 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.0439 AC: 467 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1104 AN: 68046

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.0136 Hom.: 80

Bravo AF: 0.00958

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0221 AC: 85

ESP6500AA AF: 0.00297 AC: 13

ESP6500EA AF: 0.0133 AC: 114

ExAC AF: 0.00886 AC: 1060

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hypercholesterolemia, autosomal dominant, 3 (4)
-	-	4	Hypercholesterolemia, familial, 1 (4)
-	-	3	not provided (3)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypobetalipoproteinemia (1)
1	-	-	Hypocholesterolemia (1)
-	-	-	Low density lipoprotein cholesterol level quantitative trait locus 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.7
DANN	Benign	0.95
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.78
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.028
Sift	Benign	0.36	T
Sift4G	Benign	0.48	T
Polyphen		0.0010	B
Vest4		0.099
MPC		0.28
ClinPred		0.013	T
GERP RS		-0.26
PromoterAI		0.049	Neutral
Varity_R		0.54
gMVP		0.68
Mutation Taster		=92/8	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: rs11591147; hg19: chr1-55505647;