rs3736228

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_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. 13/20 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

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

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]

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a domain LDL-receptor class A 2 (size 36) in uniprot entity LRP5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002335.4

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=0.0020527542).

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 rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.3989C>T	p.Ala1330Val	missense_variant	Exon 18 of 23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP5	ENST00000294304.12 link	c.3989C>T	p.Ala1330Val	missense_variant	Exon 18 of 23	1	NM_002335.4	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5 link	n.*2595C>T		non_coding_transcript_exon_variant	Exon 18 of 23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5 link	n.*2595C>T		3_prime_UTR_variant	Exon 18 of 23	1		ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16841

AN:

152168

Hom.:

1184

Cov.:

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.:

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.:

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33302760, 25580429, 30283887, 16355283, 18026682, 16713434, 18455228, 18349089, 17955262, 19571442, 21432225, 18058054, 22511589, 21116122) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Osteogenesis imperfecta

Benign:1

Jul 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Increased bone mineral density

Benign:1

Mar 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteoporosis with pseudoglioma

Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.24

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.4

REVEL

Benign

0.22

Sift

Benign

0.21

Sift4G

Benign

0.30

Polyphen

0.015

Vest4

0.058

MPC

0.41

ClinPred

0.0090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over