chr19-11089297-T-C

Variant names:

• chr19-11089297-T-C
• ENST00000828660.1:n.1A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000828660.1(ENSG00000307752):​n.1A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000307752 ENST00000828660.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.636
• Publications: 0 publications found

Genes affected

ENSG00000307752 (HGNC:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000828660.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR-AS1	NR_163945.1		n.363A>G		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-252T>C		upstream_gene	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.-252T>C		upstream_gene	N/A	NP_001182727.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000307752	ENST00000828660.1		n.1A>G		non_coding_transcript_exon	Exon 1 of 1
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.-252T>C		upstream_gene	N/A	ENSP00000454071.1
	LDLR	ENST00000558013.5	TSL:1	c.-252T>C		upstream_gene	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 305162 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 158486

African (AFR) AF: 0.00 AC: 0 AN: 8324

American (AMR) AF: 0.00 AC: 0 AN: 10078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10358

East Asian (EAS) AF: 0.00 AC: 0 AN: 23808

South Asian (SAS) AF: 0.00 AC: 0 AN: 18688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 189132

Other (OTH) AF: 0.00 AC: 0 AN: 19000

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.1
DANN	Benign	0.67
PhyloP100		-0.64
PromoterAI		0.0069	Neutral

Splicing

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

Other links and lift over

hg19: chr19-11199973;