rs4988321
Positions:
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1
The NM_002335.4(LRP5):c.1999G>A(p.Val667Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,614,070 control chromosomes in the GnomAD database, including 1,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.035 ( 140 hom., cov: 32)
Exomes 𝑓: 0.046 ( 1802 hom. )
Consequence
LRP5
NM_002335.4 missense
NM_002335.4 missense
Scores
2
8
8
Clinical Significance
Conservation
PhyloP100: 7.87
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 -17 ACMG points.
PM1
?
In a region_of_interest Beta-propeller 3 (size 259) in uniprot entity LRP5_HUMAN there are 46 pathogenic changes around while only 7 benign (87%) in NM_002335.4
PP2
?
Missense variant where missense usually causes diseases, LRP5
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0044097304).
BP6
?
Variant 11-68406721-G-A is Benign according to our data. Variant chr11-68406721-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 6276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68406721-G-A is described in Lovd as [Pathogenic]. Variant chr11-68406721-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-68406721-G-A is described in Lovd as [Benign]. Variant chr11-68406721-G-A is described in Lovd as [Likely_benign].
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP5 | NM_002335.4 | c.1999G>A | p.Val667Met | missense_variant | 9/23 | ENST00000294304.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.1999G>A | p.Val667Met | missense_variant | 9/23 | 1 | NM_002335.4 | P1 | |
LRP5 | ENST00000529993.5 | c.*605G>A | 3_prime_UTR_variant, NMD_transcript_variant | 9/23 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0347 AC: 5287AN: 152158Hom.: 140 Cov.: 32
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GnomAD3 exomes AF: 0.0381 AC: 9565AN: 251330Hom.: 265 AF XY: 0.0388 AC XY: 5273AN XY: 135884
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GnomAD4 exome AF: 0.0464 AC: 67886AN: 1461794Hom.: 1802 Cov.: 33 AF XY: 0.0461 AC XY: 33492AN XY: 727196
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GnomAD4 genome ? AF: 0.0347 AC: 5287AN: 152276Hom.: 140 Cov.: 32 AF XY: 0.0337 AC XY: 2507AN XY: 74452
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ALSPAC
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ESP6500AA
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ESP6500EA
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480
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:12Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4Other:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 30283887, 28222408, 15077203, 18026682, 18349089, 22025579, 18058054, 11719191, 17307038, 22511589, 21116122) - |
not provided, no classification provided | literature only | NEI Ophthalmic Genomics Laboratory, National Institutes of Health | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 06, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Osteoporosis with pseudoglioma Pathogenic:1Benign:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 16, 2001 | - - |
not provided, no classification provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Osteogenesis imperfecta Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 18, 2022 | - - |
Increased bone mineral density Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 31, 2021 | - - |
Osteoporosis;C0432252:Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 1;C1851402:Exudative vitreoretinopathy 1;C1866079:Bone mineral density quantitative trait locus 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 06, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
D
Sift4G
Benign
T
Polyphen
D
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at