GeneBe

rs549995837

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NR_163945.1(LDLR-AS1):​n.317G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

LDLR-AS1
NR_163945.1 non_coding_transcript_exon

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.28

Publications

5 publications found
Variant links:
Genes affected
LDLR-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]
LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]
LDLR Gene-Disease associations (from GenCC):
  • hypercholesterolemia, familial, 1
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
  • homozygous familial hypercholesterolemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.33).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_163945.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
LDLR-AS1
NR_163945.1
n.317G>A
non_coding_transcript_exon
Exon 1 of 1
LDLR
NM_000527.5
MANE Select
c.-206C>T
upstream_gene
N/ANP_000518.1
LDLR
NM_001195798.2
c.-206C>T
upstream_gene
N/ANP_001182727.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
LDLR
ENST00000558518.6
TSL:1 MANE Select
c.-206C>T
upstream_gene
N/AENSP00000454071.1
LDLR
ENST00000558013.5
TSL:1
c.-206C>T
upstream_gene
N/AENSP00000453346.1
LDLR
ENST00000557933.5
TSL:5
c.-206C>T
upstream_gene
N/AENSP00000453557.1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
385864
Hom.:
0
Cov.:
3
AF XY:
0.00
AC XY:
0
AN XY:
202098
African (AFR)
AF:
0.00
AC:
0
AN:
10454
American (AMR)
AF:
0.00
AC:
0
AN:
13752
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
12280
East Asian (EAS)
AF:
0.00
AC:
0
AN:
27076
South Asian (SAS)
AF:
0.00
AC:
0
AN:
34352
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
28148
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1724
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
235070
Other (OTH)
AF:
0.00
AC:
0
AN:
23008
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74456
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41560
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2
Mar 25, 2016
LDLR-LOVD, British Heart Foundation
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:literature only

Apr 11, 2016
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.33
CADD
Benign
14
DANN
Benign
0.81
PhyloP100
1.3
PromoterAI
0.082
Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs549995837; hg19: chr19-11200019; API