rs4988321

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BA1

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.035 ( 140 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1802 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:14O:2

Conservation

PhyloP100: 7.87

Publications

89 publications found

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 Gene-Disease associations (from GenCC):

bone mineral density quantitative trait locus 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
exudative vitreoretinopathy 4
Inheritance: AD, SD, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
inherited retinal dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
osteoporosis-pseudoglioma syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant osteosclerosis, Worth type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
polycystic liver disease 4 with or without kidney cysts
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal dominant osteopetrosis 1
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
exudative vitreoretinopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hyperostosis corticalis generalisata
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteosclerosis-developmental delay-craniosynostosis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
polycystic liver disease 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

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, autosomal dominant osteopetrosis 1, osteoporosis-pseudoglioma syndrome, autosomal dominant osteosclerosis, Worth type, polycystic liver disease 4 with or without kidney cysts, bone mineral density quantitative trait locus 1, osteosclerosis-developmental delay-craniosynostosis syndrome, hyperostosis corticalis generalisata, exudative vitreoretinopathy, polycystic liver disease 1, inherited retinal dystrophy.

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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6276.

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 rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.1999G>A	p.Val667Met	missense_variant	Exon 9 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.1999G>A	p.Val667Met	missense_variant	Exon 9 of 23	1	NM_002335.4	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5 link	n.*605G>A		non_coding_transcript_exon_variant	Exon 9 of 23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5 link	n.*605G>A		3_prime_UTR_variant	Exon 9 of 23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000528890.1 link	n.*174G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5287

AN:

152158

Hom.:

140

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00975

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0427

Gnomad ASJ

AF:

0.0876

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0253

Gnomad FIN

AF:

0.00990

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0517

Gnomad OTH

AF:

0.0540

GnomAD2 exomes

AF:

0.0381

AC:

9565

AN:

251330

AF XY:

0.0388

show subpopulations

Gnomad AFR exome

AF:

0.00800

Gnomad AMR exome

AF:

0.0325

Gnomad ASJ exome

AF:

0.0932

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.0525

Gnomad OTH exome

AF:

0.0548

GnomAD4 exome

AF:

0.0464

AC:

67886

AN:

1461794

Hom.:

1802

Cov.:

AF XY:

0.0461

AC XY:

33492

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00890

AC:

298

AN:

33478

American (AMR)

AF:

0.0348

AC:

1556

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0924

AC:

2414

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0269

AC:

2322

AN:

86258

European-Finnish (FIN)

AF:

0.0130

AC:

694

AN:

53376

Middle Eastern (MID)

AF:

0.0954

AC:

550

AN:

5768

European-Non Finnish (NFE)

AF:

0.0515

AC:

57290

AN:

1111966

Other (OTH)

AF:

0.0457

AC:

2758

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3691

7382

11073

14764

18455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2122

4244

6366

8488

10610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0347

AC:

5287

AN:

152276

Hom.:

140

Cov.:

AF XY:

0.0337

AC XY:

2507

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00972

AC:

404

AN:

41560

American (AMR)

AF:

0.0426

AC:

651

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0876

AC:

304

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0257

AC:

124

AN:

4824

European-Finnish (FIN)

AF:

0.00990

AC:

105

AN:

10608

Middle Eastern (MID)

AF:

0.116

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0517

AC:

3514

AN:

68016

Other (OTH)

AF:

0.0534

AC:

113

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

275

550

824

1099

1374

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0495

Hom.:

944

Bravo

AF:

0.0375

TwinsUK

AF:

0.0515

AC:

191

ALSPAC

AF:

0.0477

AC:

184

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.0559

AC:

480

ExAC

AF:

0.0375

AC:

4557

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0580

EpiControl

AF:

0.0569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:14Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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: 30283887, 28222408, 15077203, 18026682, 18349089, 22025579, 18058054, 11719191, 17307038, 22511589, 21116122) -

Dec 06, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Osteoporosis with pseudoglioma

Pathogenic:1Benign:1Other:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 02, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2014

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

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

- -

Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 1;C1851402:Exudative vitreoretinopathy 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts

Benign:1

Feb 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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;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

May 06, 2022

Fulgent Genetics, Fulgent Genetics

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

0.14

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0044

MetaSVM

Uncertain

0.0064

MutationAssessor

Uncertain

2.4

PhyloP100

7.9

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.55

Sift

Benign

0.039

Sift4G

Benign

0.093

Polyphen

0.99

Vest4

0.17

MPC

0.43

ClinPred

0.049

GERP RS

4.1

Varity_R

0.13

gMVP

0.71

Mutation Taster

=32/68

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over