rs28362263

Variant names:

• chr1-55058182-G-A
• rs28362263
• NM_174936.4:c.1327G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55058182-G-A
• chr1-55058182-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.1327G>A​(p.Ala443Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 1,613,318 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (186 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (151 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:15
• Conservation: PhyloP100: 1.40
• Publications: 54 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=0.0014311075).
• BP6: Variant 1-55058182-G-A is Benign according to our data. Variant chr1-55058182-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0919 is higher than 0.05.

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.1327G>A	p.Ala443Thr	missense	Exon 8 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.1450G>A	p.Ala484Thr	missense	Exon 9 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1327G>A	p.Ala443Thr	missense	Exon 8 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.1327G>A	p.Ala443Thr	missense	Exon 8 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1684G>A	p.Ala562Thr	missense	Exon 8 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1450G>A	p.Ala484Thr	missense	Exon 9 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4136 AN: 152204 Hom.: 186 Cov.: 33

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.00719 AC: 1797 AN: 249780 AF XY: 0.00520

Gnomad AFR exome AF: 0.0977

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.000763

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00277 AC: 4042 AN: 1460996 Hom.: 151 Cov.: 33 AF XY: 0.00239 AC XY: 1738 AN XY: 726824

African (AFR) AF: 0.0927 AC: 3101 AN: 33470

American (AMR) AF: 0.00487 AC: 218 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26134

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86252

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52616

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5752

European-Non Finnish (NFE) AF: 0.000272 AC: 302 AN: 1111964

Other (OTH) AF: 0.00515 AC: 311 AN: 60384

GnomAD4 genome AF: 0.0272 AC: 4138 AN: 152322 Hom.: 186 Cov.: 33 AF XY: 0.0258 AC XY: 1920 AN XY: 74500

African (AFR) AF: 0.0943 AC: 3920 AN: 41558

American (AMR) AF: 0.00901 AC: 138 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68022

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.00990 Hom.: 135

Bravo AF: 0.0305

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0837 AC: 369

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00884 AC: 1073

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hypercholesterolemia, autosomal dominant, 3 (5)
1	1	1	Hypercholesterolemia, familial, 1 (3)
-	-	3	not provided (3)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypobetalipoproteinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.71
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.043
Sift	Benign	0.53	T
Sift4G	Benign	0.60	T
Polyphen		0.0040	B
Vest4		0.022
MVP		0.32
MPC		0.22
ClinPred		0.0012	T
GERP RS		-6.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
gMVP		0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs28362263; hg19: chr1-55523855; COSMIC: COSV56165606;