ENST00000559340.2:n.-119A>C

Variant names:

• chr19-11089299-G-C
• NR_163945.1:n.361C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000559340.2(LDLR):​n.-250G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000647 in 308,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: LDLR ENST00000559340.2 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.573

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.-250G>C		upstream_gene_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.-250G>C		upstream_gene_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000647 AC: 2 AN: 308902 Hom.: 0 AF XY: 0.00000623 AC XY: 1 AN XY: 160620

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000834

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.6
DANN	Benign	0.58

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11199975;