rs4988322
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_002335.4(LRP5):c.2318+6T>C 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 0.0676 in 1,611,592 control chromosomes in the GnomAD database, including 3,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.064 ( 371 hom., cov: 31)
Exomes 𝑓: 0.068 ( 3555 hom. )
Consequence
LRP5
NM_002335.4 splice_donor_region, intron
NM_002335.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.001634
2
Clinical Significance
Conservation
PhyloP100: -1.41
Genes affected
LRP5 (HGNC:6697): (LDL receptor related protein 5) This gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with type 1 diabetes mellitus in humans. This protein plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene. Mutations in this gene also cause familial exudative vitreoretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
Variant 11-68410146-T-C is Benign according to our data. Variant chr11-68410146-T-C is described in ClinVar as [Benign]. Clinvar id is 258636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68410146-T-C is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0691 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP5 | NM_002335.4 | c.2318+6T>C | splice_donor_region_variant, intron_variant | ENST00000294304.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.2318+6T>C | splice_donor_region_variant, intron_variant | 1 | NM_002335.4 | P1 | |||
LRP5 | ENST00000529993.5 | c.*924+6T>C | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 1 | |||||
LRP5 | ENST00000528714.1 | n.112+6T>C | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0635 AC: 9659AN: 152112Hom.: 370 Cov.: 31
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GnomAD3 exomes AF: 0.0585 AC: 14432AN: 246616Hom.: 448 AF XY: 0.0588 AC XY: 7864AN XY: 133840
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GnomAD4 exome AF: 0.0681 AC: 99338AN: 1459362Hom.: 3555 Cov.: 34 AF XY: 0.0672 AC XY: 48768AN XY: 726062
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GnomAD4 genome ? AF: 0.0635 AC: 9669AN: 152230Hom.: 371 Cov.: 31 AF XY: 0.0618 AC XY: 4602AN XY: 74422
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ClinVar
Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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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