19-11131833-C-A
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_000527.5(LDLR):c.*517C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000894 in 433,124 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0021 ( 2 hom., cov: 31)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
LDLR
NM_000527.5 3_prime_UTR
NM_000527.5 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0560
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 19-11131833-C-A is Benign according to our data. Variant chr19-11131833-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 889991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAd4 at 2 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.*517C>A | 3_prime_UTR_variant | 18/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.*517C>A | 3_prime_UTR_variant | 18/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00207 AC: 315AN: 152152Hom.: 2 Cov.: 31
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GnomAD4 exome AF: 0.000242 AC: 68AN: 280854Hom.: 0 Cov.: 0 AF XY: 0.000264 AC XY: 39AN XY: 147544
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GnomAD4 genome AF: 0.00209 AC: 319AN: 152270Hom.: 2 Cov.: 31 AF XY: 0.00199 AC XY: 148AN XY: 74448
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Familial hypercholesterolemia Benign:1
Benign, criteria provided, single submitter | clinical testing | GENinCode PLC | Jan 25, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at