rs10417394
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP7BS1
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.498C>T (p.Ala166=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (spcification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA043710/MONDO:0007750/013
Frequency
Consequence
ENST00000558518.6 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.498C>T | p.Ala166= | synonymous_variant | 4/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.498C>T | p.Ala166= | synonymous_variant | 4/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00141 AC: 214AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000358 AC: 90AN: 251292Hom.: 0 AF XY: 0.000294 AC XY: 40AN XY: 135880
GnomAD4 exome AF: 0.000126 AC: 184AN: 1461690Hom.: 1 Cov.: 33 AF XY: 0.000110 AC XY: 80AN XY: 727156
GnomAD4 genome AF: 0.00143 AC: 218AN: 152364Hom.: 0 Cov.: 33 AF XY: 0.00140 AC XY: 104AN XY: 74506
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:1Benign:2
Benign, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Aug 30, 2024 | The NM_000527.5(LDLR):c.498C>T (p.Ala166=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (spcification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. - |
Familial hypercholesterolemia Benign:3
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 17, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 25, 2019 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 07, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2017 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at