rs72658888

Variant names:

• chr1-55039551-G-A
• rs72658888
• NM_174936.4:c.-287G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55039551-G-A
• chr1-55039551-G-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.-287G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00979 in 546,320 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (44 hom.)
• Consequence: PCSK9 NM_174936.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.184
• Publications: 6 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 (BayesDel_noAF=-0.53).
• BP6: Variant 1-55039551-G-A is Benign according to our data. Variant chr1-55039551-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 265911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0094 (1432/152350) while in subpopulation AMR AF = 0.0239 (366/15310). AF 95% confidence interval is 0.0219. There are 21 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.-287G>A		5_prime_UTR	Exon 1 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.-287G>A		5_prime_UTR	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.-287G>A		5_prime_UTR	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.-287G>A		5_prime_UTR	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.71G>A	p.Arg24Gln	missense	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.-287G>A		5_prime_UTR	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1433 AN: 152232 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00994 AC: 3916 AN: 393970 Hom.: 44 Cov.: 2 AF XY: 0.0100 AC XY: 2062 AN XY: 205878

African (AFR) AF: 0.00160 AC: 17 AN: 10644

American (AMR) AF: 0.0201 AC: 327 AN: 16262

Ashkenazi Jewish (ASJ) AF: 0.00381 AC: 46 AN: 12066

East Asian (EAS) AF: 0.0000375 AC: 1 AN: 26696

South Asian (SAS) AF: 0.0133 AC: 545 AN: 40986

European-Finnish (FIN) AF: 0.0108 AC: 278 AN: 25708

Middle Eastern (MID) AF: 0.00345 AC: 6 AN: 1738

European-Non Finnish (NFE) AF: 0.0103 AC: 2440 AN: 236814

Other (OTH) AF: 0.0111 AC: 256 AN: 23056

GnomAD4 genome AF: 0.00940 AC: 1432 AN: 152350 Hom.: 21 Cov.: 33 AF XY: 0.00993 AC XY: 740 AN XY: 74496

African (AFR) AF: 0.00216 AC: 90 AN: 41586

American (AMR) AF: 0.0239 AC: 366 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4826

European-Finnish (FIN) AF: 0.00800 AC: 85 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 800 AN: 68030

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00969 Hom.: 1

Bravo AF: 0.00859

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, autosomal dominant, 3 (1)
-	-	1	Hypercholesterolemia, familial, 1 (1)
-	-	1	Hypobetalipoproteinemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		0.18
PromoterAI		-0.064	Neutral
Mutation Taster		=300/0	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: rs72658888; hg19: chr1-55505224;