rs28385701

Variant names:

• chr1-55039978-C-T
• rs28385701
• NM_174936.4:c.141C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-55039978-C-T
• chr1-55039978-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001407246.1(PCSK9):​c.-594C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 1,580,712 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0083 (8 hom., cov: 34)
  • Exomes 𝑓: 0.0093 (100 hom.)
• Consequence: PCSK9 NM_001407246.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:16
• Conservation: PhyloP100: -1.90
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-55039978-C-T is Benign according to our data. Variant chr1-55039978-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262902.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00833 (1270/152386) while in subpopulation SAS AF = 0.0134 (65/4834). AF 95% confidence interval is 0.0108. There are 8 homozygotes in GnomAd4. There are 658 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

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.141C>T	p.Ser47Ser	synonymous	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407246.1		c.-594C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001394175.1	A0A669KBG0
	PCSK9	NM_001407240.1		c.141C>T	p.Ser47Ser	synonymous	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.141C>T	p.Ser47Ser	synonymous	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.498C>T	p.Ser166Ser	synonymous	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.141C>T	p.Ser47Ser	synonymous	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1271 AN: 152268 Hom.: 8 Cov.: 34

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0100 AC: 1973 AN: 196516 AF XY: 0.0102

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.0000675

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00927 AC: 13238 AN: 1428326 Hom.: 100 Cov.: 31 AF XY: 0.00947 AC XY: 6697 AN XY: 707412

African (AFR) AF: 0.00165 AC: 54 AN: 32778

American (AMR) AF: 0.0102 AC: 413 AN: 40316

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 540 AN: 25484

East Asian (EAS) AF: 0.0000528 AC: 2 AN: 37872

South Asian (SAS) AF: 0.0127 AC: 1031 AN: 81332

European-Finnish (FIN) AF: 0.0120 AC: 605 AN: 50398

Middle Eastern (MID) AF: 0.0323 AC: 155 AN: 4798

European-Non Finnish (NFE) AF: 0.00896 AC: 9823 AN: 1096232

Other (OTH) AF: 0.0104 AC: 615 AN: 59116

GnomAD4 genome AF: 0.00833 AC: 1270 AN: 152386 Hom.: 8 Cov.: 34 AF XY: 0.00883 AC XY: 658 AN XY: 74520

African (AFR) AF: 0.00161 AC: 67 AN: 41598

American (AMR) AF: 0.0120 AC: 183 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0134 AC: 65 AN: 4834

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10632

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 693 AN: 68038

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0104 Hom.: 16

Bravo AF: 0.00818

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Hypercholesterolemia, autosomal dominant, 3 (4)
-	2	2	Hypercholesterolemia, familial, 1 (4)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial hypercholesterolemia (1)
-	-	1	Hypobetalipoproteinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.1
DANN	Benign	0.96
PhyloP100		-1.9
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs28385701; hg19: chr1-55505651;