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GeneBe

rs3736228

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002335.4(LRP5):c.3989C>T(p.Ala1330Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,611,778 control chromosomes in the GnomAD database, including 17,351 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1330A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 1182 hom., cov: 33)
Exomes 𝑓: 0.14 ( 16169 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

4
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.478
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 Benign. Variant got -19 ACMG points.

PP2
Missense variant where missense usually causes diseases, LRP5
BP4
Computational evidence support a benign effect (MetaRNN=0.0020527542).
BP6
Variant 11-68433827-C-T is Benign according to our data. Variant chr11-68433827-C-T is described in ClinVar as [Benign]. Clinvar id is 258640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68433827-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-68433827-C-T is described in Lovd as [Benign]. Variant chr11-68433827-C-T is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRP5NM_002335.4 linkuse as main transcriptc.3989C>T p.Ala1330Val missense_variant 18/23 ENST00000294304.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRP5ENST00000294304.12 linkuse as main transcriptc.3989C>T p.Ala1330Val missense_variant 18/231 NM_002335.4 P1
LRP5ENST00000529993.5 linkuse as main transcriptc.*2595C>T 3_prime_UTR_variant, NMD_transcript_variant 18/231

Frequencies

GnomAD3 genomes
AF:
0.111
AC:
16841
AN:
152168
Hom.:
1184
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0427
Gnomad AMI
AF:
0.294
Gnomad AMR
AF:
0.156
Gnomad ASJ
AF:
0.107
Gnomad EAS
AF:
0.205
Gnomad SAS
AF:
0.130
Gnomad FIN
AF:
0.0389
Gnomad MID
AF:
0.168
Gnomad NFE
AF:
0.141
Gnomad OTH
AF:
0.134
GnomAD3 exomes
AF:
0.134
AC:
32608
AN:
243164
Hom.:
2508
AF XY:
0.132
AC XY:
17593
AN XY:
132822
show subpopulations
Gnomad AFR exome
AF:
0.0433
Gnomad AMR exome
AF:
0.187
Gnomad ASJ exome
AF:
0.115
Gnomad EAS exome
AF:
0.204
Gnomad SAS exome
AF:
0.130
Gnomad FIN exome
AF:
0.0434
Gnomad NFE exome
AF:
0.139
Gnomad OTH exome
AF:
0.137
GnomAD4 exome
AF:
0.144
AC:
209942
AN:
1459492
Hom.:
16169
Cov.:
33
AF XY:
0.143
AC XY:
104076
AN XY:
726148
show subpopulations
Gnomad4 AFR exome
AF:
0.0373
Gnomad4 AMR exome
AF:
0.181
Gnomad4 ASJ exome
AF:
0.116
Gnomad4 EAS exome
AF:
0.242
Gnomad4 SAS exome
AF:
0.132
Gnomad4 FIN exome
AF:
0.0457
Gnomad4 NFE exome
AF:
0.149
Gnomad4 OTH exome
AF:
0.133
GnomAD4 genome
AF:
0.111
AC:
16846
AN:
152286
Hom.:
1182
Cov.:
33
AF XY:
0.108
AC XY:
8013
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.0427
Gnomad4 AMR
AF:
0.156
Gnomad4 ASJ
AF:
0.107
Gnomad4 EAS
AF:
0.205
Gnomad4 SAS
AF:
0.130
Gnomad4 FIN
AF:
0.0389
Gnomad4 NFE
AF:
0.141
Gnomad4 OTH
AF:
0.134
Alfa
AF:
0.140
Hom.:
3093
Bravo
AF:
0.122
TwinsUK
AF:
0.156
AC:
580
ALSPAC
AF:
0.149
AC:
576
ESP6500AA
AF:
0.0475
AC:
209
ESP6500EA
AF:
0.141
AC:
1209
ExAC
AF:
0.128
AC:
15545
Asia WGS
AF:
0.140
AC:
488
AN:
3478
EpiCase
AF:
0.145
EpiControl
AF:
0.143

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 33302760, 25580429, 30283887, 16355283, 18026682, 16713434, 18455228, 18349089, 17955262, 19571442, 21432225, 18058054, 22511589, 21116122) -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncMay 24, 2018- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
not specified Benign:3
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 14, 2015- -
Osteogenesis imperfecta Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJul 18, 2022- -
Increased bone mineral density Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMar 31, 2021- -
Osteoporosis with pseudoglioma Benign:1
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.37
Cadd
Benign
19
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.52
D
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.30
N
LIST_S2
Uncertain
0.89
D
MetaRNN
Benign
0.0021
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.24
N
MutationTaster
Benign
0.99
P
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.22
Sift
Benign
0.21
T
Sift4G
Benign
0.30
T
Polyphen
0.015
B
Vest4
0.058
MPC
0.41
ClinPred
0.0090
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.029
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs3736228; hg19: chr11-68201295; COSMIC: COSV53725745; COSMIC: COSV53725745; API