11-68425226-A-G
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 5P and 8B. PM1PM2PP2BP4_StrongBS1
The NM_002335.4(LRP5):āc.3361A>Gā(p.Asn1121Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,612,698 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: š 0.00039 ( 0 hom., cov: 33)
Exomes š: 0.00020 ( 0 hom. )
Consequence
LRP5
NM_002335.4 missense
NM_002335.4 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 8.70
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
In a repeat LDL-receptor class B 18 (size 44) in uniprot entity LRP5_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_002335.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the LRP5 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 71 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 1.6684 (below the threshold of 3.09). Trascript score misZ: 3.6986 (above the threshold of 3.09). GenCC associations: The gene is linked to exudative vitreoretinopathy 4, polycystic liver disease 4 with or without kidney cysts, polycystic liver disease 1, exudative vitreoretinopathy, osteosclerosis-developmental delay-craniosynostosis syndrome, bone mineral density quantitative trait locus 1, autosomal dominant osteopetrosis 1, hyperostosis corticalis generalisata, osteoporosis-pseudoglioma syndrome, autosomal dominant osteosclerosis, Worth type, inherited retinal dystrophy.
BP4
Computational evidence support a benign effect (MetaRNN=0.021463394).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000394 (60/152164) while in subpopulation EAS AF= 0.0104 (54/5170). AF 95% confidence interval is 0.00822. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.3361A>G | p.Asn1121Asp | missense_variant | Exon 15 of 23 | 1 | NM_002335.4 | ENSP00000294304.6 | ||
LRP5 | ENST00000529993.5 | n.*1967A>G | non_coding_transcript_exon_variant | Exon 15 of 23 | 1 | ENSP00000436652.1 | ||||
LRP5 | ENST00000529993.5 | n.*1967A>G | 3_prime_UTR_variant | Exon 15 of 23 | 1 | ENSP00000436652.1 |
Frequencies
GnomAD3 genomes AF: 0.000395 AC: 60AN: 152046Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
60
AN:
152046
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000640 AC: 160AN: 250134Hom.: 0 AF XY: 0.000620 AC XY: 84AN XY: 135420
GnomAD3 exomes
AF:
AC:
160
AN:
250134
Hom.:
AF XY:
AC XY:
84
AN XY:
135420
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000202 AC: 295AN: 1460534Hom.: 0 Cov.: 35 AF XY: 0.000202 AC XY: 147AN XY: 726682
GnomAD4 exome
AF:
AC:
295
AN:
1460534
Hom.:
Cov.:
35
AF XY:
AC XY:
147
AN XY:
726682
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000394 AC: 60AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34AN XY: 74400
GnomAD4 genome
AF:
AC:
60
AN:
152164
Hom.:
Cov.:
33
AF XY:
AC XY:
34
AN XY:
74400
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
80
Asia WGS
AF:
AC:
8
AN:
3478
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Exudative vitreoretinopathy 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Exudative vitreoretinopathy 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1-Supporting => BS1 downgraded in strength to supporting. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2020 | Reported previously in individuals with familial exudative vitreoretinopathy, but some individuals were reported to have causative variants in other genes and the variant was inherited from an unaffected parent in multiple families (Qin et al., 2005; Yang et al., 2012; Seo et al., 2015; Tang et al., 2017; Li et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26244290, 29181528, 28251098, 23077402, 15981244, 30452590, 31169861, 30097784) - |
Osteogenesis imperfecta Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 16, 2020 | - - |
Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 1;C1866079:Bone mineral density quantitative trait locus 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 29, 2024 | - - |
LRP5-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 24, 2024 | The LRP5 c.3361A>G variant is predicted to result in the amino acid substitution p.Asn1121Asp. This variant has been reported in individuals with familial exudative vitreoretinopathy; however, it has also been detected in unaffected parents and in individuals in whom another causative variant was identified (see, for example, Qin et al. 2005. PubMed ID: 15981244; Li et al. 2018. PubMed ID: 30452590; Kondo et al. 2024. PubMed ID: 38881609). This variant is reported in 0.79% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at