dbSNP rs879254364: LDLR-AS1:n.267G>A (chr19-11089393-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NR_163945.1(LDLR-AS1):n.267G>A variant causes a non coding transcript exon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LDLR-AS1
NR_163945.1 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:3

Conservation

PhyloP100: 3.66

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-AS1 links:

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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Genomics England PanelApp
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

ENSG00000307752 (HGNC:):

ENSG00000307752 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.11).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR-AS1	NR_163945.1		n.267G>A	non_coding_transcript_exon	Exon 1 of 1
LDLR	NM_000527.5	MANE Select	c.-156C>T	upstream_gene	N/A	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.-156C>T	upstream_gene	N/A	NP_001182727.1	P01130-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.-156C>T	upstream_gene	N/A	ENSP00000454071.1	P01130-1
LDLR	ENST00000558013.5	TSL:1	c.-156C>T	upstream_gene	N/A	ENSP00000453346.1	P01130-5
LDLR	ENST00000557933.5	TSL:5	c.-156C>T	upstream_gene	N/A	ENSP00000453557.1	H0YMD1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

455202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

238662

African (AFR)

AF:

0.00

AC:

AN:

12466

American (AMR)

AF:

0.00

AC:

AN:

18882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13794

East Asian (EAS)

AF:

0.00

AC:

AN:

30252

South Asian (SAS)

AF:

0.00

AC:

AN:

45572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1950

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

275620

Other (OTH)

AF:

0.00

AC:

AN:

26040

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (3)

Cardiovascular phenotype (1)

Familial hypercholesterolemia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

3.7

PromoterAI

-0.080

Neutral

(source)

Mutation Taster

=82/218

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over