11-68348021-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_002335.4(LRP5):c.266A>G(p.Gln89Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00951 in 1,614,176 control chromosomes in the GnomAD database, including 295 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. Q89Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0091 ( 32 hom., cov: 33)

Exomes 𝑓: 0.0096 ( 263 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.99

Publications

58 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 -17 ACMG points.

PM1

In a region_of_interest Beta-propeller 1 (size 256) in uniprot entity LRP5_HUMAN there are 26 pathogenic changes around while only 5 benign (84%) 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, 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=0.0024719536).

BP6

Variant 11-68348021-A-G is Benign according to our data. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in CliVar as Benign. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.266A>G	p.Gln89Arg	missense_variant	Exon 2 of 23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 link	c.266A>G	p.Gln89Arg	missense_variant	Exon 2 of 23	1	NM_002335.4	ENSP00000294304.6		O75197
LRP5	ENST00000529993.5 link	n.266A>G		non_coding_transcript_exon_variant	Exon 2 of 23	1		ENSP00000436652.1		E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.00914

AC:

1391

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0810

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00541

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0195

AC:

4894

AN:

251332

AF XY:

0.0162

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.0649

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0934

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00542

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.00955

AC:

13962

AN:

1461840

Hom.:

263

Cov.:

AF XY:

0.00898

AC XY:

6531

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

33480

American (AMR)

AF:

0.0606

AC:

2712

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.0768

AC:

3050

AN:

39700

South Asian (SAS)

AF:

0.00556

AC:

480

AN:

86258

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00612

AC:

6811

AN:

1112008

Other (OTH)

AF:

0.0113

AC:

680

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

951

1903

2854

3806

4757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.00914

AC:

1393

AN:

152336

Hom.:

Cov.:

AF XY:

0.00944

AC XY:

703

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41586

American (AMR)

AF:

0.0284

AC:

434

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.0812

AC:

420

AN:

5174

South Asian (SAS)

AF:

0.00456

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00541

AC:

368

AN:

68030

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

142

214

285

356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00991

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.0174

AC:

2109

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00480

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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: 31169861, 30513533, 28378289, 16115379, 21528003, 17955262, 22511589) -

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

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 06, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta

Benign:1

Jul 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.18

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.27

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-1.0

PhyloP100

2.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.36

REVEL

Benign

0.26

Sift

Benign

0.88

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.12

MPC

0.44

ClinPred

0.021

GERP RS

4.5

Varity_R

0.11

gMVP

0.71

Mutation Taster

=79/21

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