ENST00000913405.1:c.-97G>T

Variant names:

• chr19-11089452-G-T
• rs944580031
• ENST00000913405.1:c.-97G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The ENST00000913405.1(LDLR):​c.-97G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000627 in 798,010 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 Conflicting classifications of pathogenicity (no stars). The gene LDLR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: LDLR ENST00000913405.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.140
• Publications: 0 publications found

Genes affected

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-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]

ENSG00000307752 (HGNC:):

ACMG classification

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-11089452-G-T is Benign according to our data. Variant chr19-11089452-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 892549.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000913405.1. 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
	LDLR-AS1	NR_163945.1		n.208C>A		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-97G>T		upstream_gene	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.-97G>T		upstream_gene	N/A	NP_001182727.1	P01130-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000913405.1		c.-97G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000583464.1
	LDLR	ENST00000856646.1		c.-97G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000526705.1
	LDLR	ENST00000913412.1		c.-97G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000583471.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000627 AC: 5 AN: 798010 Hom.: 0 Cov.: 11 AF XY: 0.00000724 AC XY: 3 AN XY: 414428

African (AFR) AF: 0.00 AC: 0 AN: 20622

American (AMR) AF: 0.00 AC: 0 AN: 37228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20036

East Asian (EAS) AF: 0.000141 AC: 5 AN: 35454

South Asian (SAS) AF: 0.00 AC: 0 AN: 68474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2804

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 531444

Other (OTH) AF: 0.00 AC: 0 AN: 37860

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Familial hypercholesterolemia (1)
-	1	-	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.3
DANN	Benign	0.80
PhyloP100		0.14
PromoterAI		-0.73	Under-expression

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: rs944580031; hg19: chr19-11200128;