rs72658859
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong
The NM_000527.5(LDLR):c.940+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,603,942 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 Likely benign (★★).
Frequency
Consequence
NM_000527.5 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.940+16G>A | intron_variant | Intron 6 of 17 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000283 AC: 43AN: 152116Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000136 AC: 34AN: 250436Hom.: 0 AF XY: 0.000148 AC XY: 20AN XY: 135346
GnomAD4 exome AF: 0.000260 AC: 378AN: 1451826Hom.: 0 Cov.: 32 AF XY: 0.000284 AC XY: 205AN XY: 722278
GnomAD4 genome AF: 0.000283 AC: 43AN: 152116Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 26AN XY: 74292
ClinVar
Submissions by phenotype
not specified Benign:1
Variant summary: LDLR c.940+16G>A alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 250436 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00014 vs 0.0013), allowing no conclusion about variant significance. c.940+16G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g., Chmara_2010, Noto_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20145306, 35339733). ClinVar contains an entry for this variant (Variation ID: 251545). Based on the evidence outlined above, the variant was classified as likely benign. -
Hypercholesterolemia, familial, 1 Benign:1
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not provided Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Familial hypercholesterolemia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at