11-68425226-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 5P and 8B. PM1PM2PP2BP4_StrongBS1

The NM_002335.4(LRP5):ā€‹c.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

Scores

1
6
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 8.70
Variant links:
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 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

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRP5NM_002335.4 linkc.3361A>G p.Asn1121Asp missense_variant Exon 15 of 23 ENST00000294304.12 NP_002326.2 O75197

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRP5ENST00000294304.12 linkc.3361A>G p.Asn1121Asp missense_variant Exon 15 of 23 1 NM_002335.4 ENSP00000294304.6 O75197
LRP5ENST00000529993.5 linkn.*1967A>G non_coding_transcript_exon_variant Exon 15 of 23 1 ENSP00000436652.1 E9PHY1
LRP5ENST00000529993.5 linkn.*1967A>G 3_prime_UTR_variant Exon 15 of 23 1 ENSP00000436652.1 E9PHY1

Frequencies

GnomAD3 genomes
AF:
0.000395
AC:
60
AN:
152046
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0104
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000640
AC:
160
AN:
250134
Hom.:
0
AF XY:
0.000620
AC XY:
84
AN XY:
135420
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00794
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000654
GnomAD4 exome
AF:
0.000202
AC:
295
AN:
1460534
Hom.:
0
Cov.:
35
AF XY:
0.000202
AC XY:
147
AN XY:
726682
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00579
Gnomad4 SAS exome
AF:
0.000417
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.000414
GnomAD4 genome
AF:
0.000394
AC:
60
AN:
152164
Hom.:
0
Cov.:
33
AF XY:
0.000457
AC XY:
34
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0104
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000409
Hom.:
0
Bravo
AF:
0.000378
ExAC
AF:
0.000659
AC:
80
Asia WGS
AF:
0.00231
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 submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Uncertain significance, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsMay 31, 2018This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2025- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 09, 2020Reported 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 submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMar 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 29, 2024- -
LRP5-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 24, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.69
T
MetaRNN
Benign
0.021
T
MetaSVM
Uncertain
0.074
D
MutationAssessor
Benign
1.3
L
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.6
N
REVEL
Uncertain
0.61
Sift
Benign
0.16
T
Sift4G
Benign
0.42
T
Polyphen
0.41
B
Vest4
0.90
MVP
0.83
MPC
0.47
ClinPred
0.12
T
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.17
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80358317; hg19: chr11-68192694; API