rs371561646
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_015627.3(LDLRAP1):c.344+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,608,248 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).
Frequency
Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
LDLRAP1
NM_015627.3 splice_donor_region, intron
NM_015627.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001576
2
Clinical Significance
Conservation
PhyloP100: -7.49
Genes affected
LDLRAP1 (HGNC:18640): (low density lipoprotein receptor adaptor protein 1) The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
?
Variant 1-25554976-C-T is Benign according to our data. Variant chr1-25554976-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567026.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLRAP1 | NM_015627.3 | c.344+4C>T | splice_donor_region_variant, intron_variant | ENST00000374338.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLRAP1 | ENST00000374338.5 | c.344+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_015627.3 | P1 | |||
LDLRAP1 | ENST00000462394.1 | n.92+4C>T | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 | |||||
LDLRAP1 | ENST00000488127.1 | n.814+4C>T | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000210 AC: 32AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000838 AC: 21AN: 250700Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135522
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GnomAD4 exome AF: 0.0000330 AC: 48AN: 1455892Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 20AN XY: 724626
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GnomAD4 genome ? AF: 0.000210 AC: 32AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 23, 2023 | - - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Hypercholesterolemia, familial, 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 02, 2021 | This sequence change falls in intron 3 of the LDLRAP1 gene. It does not directly change the encoded amino acid sequence of the LDLRAP1 protein. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs371561646, ExAC 0.07%). This variant has not been reported in the literature in individuals affected with LDLRAP1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2022 | 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:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at