rs41291054
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2
The NM_015627.3(LDLRAP1):c.672C>T(p.Ser224Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,996 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_015627.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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LDLRAP1 | ENST00000374338.5 | c.672C>T | p.Ser224Ser | synonymous_variant | Exon 7 of 9 | 1 | NM_015627.3 | ENSP00000363458.4 | ||
LDLRAP1 | ENST00000484476.5 | n.394C>T | non_coding_transcript_exon_variant | Exon 2 of 4 | 1 | |||||
LDLRAP1 | ENST00000474283.1 | n.83C>T | non_coding_transcript_exon_variant | Exon 1 of 3 | 3 | |||||
LDLRAP1 | ENST00000488127.1 | n.1142C>T | non_coding_transcript_exon_variant | Exon 6 of 7 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00183 AC: 278AN: 152238Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00144 AC: 361AN: 250944Hom.: 3 AF XY: 0.00143 AC XY: 194AN XY: 135736
GnomAD4 exome AF: 0.00304 AC: 4440AN: 1461640Hom.: 9 Cov.: 33 AF XY: 0.00297 AC XY: 2159AN XY: 727132
GnomAD4 genome AF: 0.00182 AC: 278AN: 152356Hom.: 2 Cov.: 33 AF XY: 0.00161 AC XY: 120AN XY: 74504
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 4 Uncertain:1Benign:3
This is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved and has a PopMax FAF which is greater than expected for this disorder. Therefore this variant has been classified as Likely Benign (BS1, BP4, BP7). -
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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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Benign:2
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Variant summary: The LDLRAP1 c.672C>T (p.Ser224Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may introduce an SRp40 ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.0014085 (170/120692 control chromosomes [1 homozygote]), which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic LDLRAP1 variant (0.0007906), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
LDLRAP1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
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