rs314776

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002335.4(LRP5):c.884-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,613,252 control chromosomes in the GnomAD database, including 139,962 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 18654 hom., cov: 29)

Exomes 𝑓: 0.39 ( 121308 hom. )

Consequence

LRP5
NM_002335.4 splice_region, intron

Scores

Splicing: ADA: 0.000005640

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.249

Publications

16 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 11-68365567-T-C is Benign according to our data. Variant chr11-68365567-T-C is described in ClinVar as Benign. ClinVar VariationId is 258642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.884-4T>C		splice_region_variant, intron_variant	Intron 4 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 link	c.884-4T>C		splice_region_variant, intron_variant	Intron 4 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5 link	n.884-4T>C		splice_region_variant, intron_variant	Intron 4 of 22	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes

AF:

0.467

AC:

70891

AN:

151690

Hom.:

18618

Cov.:

show subpopulations

Gnomad AFR

AF:

0.694

Gnomad AMI

AF:

0.642

Gnomad AMR

AF:

0.496

Gnomad ASJ

AF:

0.389

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.406

Gnomad OTH

AF:

0.446

GnomAD2 exomes

AF:

0.378

AC:

94789

AN:

250626

AF XY:

0.360

show subpopulations

Gnomad AFR exome

AF:

0.699

Gnomad AMR exome

AF:

0.535

Gnomad ASJ exome

AF:

0.382

Gnomad EAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.270

Gnomad NFE exome

AF:

0.404

Gnomad OTH exome

AF:

0.400

GnomAD4 exome

AF:

0.395

AC:

576786

AN:

1461444

Hom.:

121308

Cov.:

AF XY:

0.386

AC XY:

280961

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.712

AC:

23832

AN:

33474

American (AMR)

AF:

0.531

AC:

23731

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

10151

AN:

26132

East Asian (EAS)

AF:

0.0935

AC:

3712

AN:

39700

South Asian (SAS)

AF:

0.172

AC:

14866

AN:

86230

European-Finnish (FIN)

AF:

0.275

AC:

14664

AN:

53384

Middle Eastern (MID)

AF:

0.446

AC:

2561

AN:

5736

European-Non Finnish (NFE)

AF:

0.413

AC:

459061

AN:

1111700

Other (OTH)

AF:

0.401

AC:

24208

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

18208

36416

54623

72831

91039

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14102

28204

42306

56408

70510

<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:

0.468

AC:

70973

AN:

151808

Hom.:

18654

Cov.:

AF XY:

0.456

AC XY:

33840

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.694

AC:

28695

AN:

41366

American (AMR)

AF:

0.496

AC:

7559

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

1346

AN:

3464

East Asian (EAS)

AF:

0.110

AC:

569

AN:

5162

South Asian (SAS)

AF:

0.174

AC:

838

AN:

4814

European-Finnish (FIN)

AF:

0.260

AC:

2747

AN:

10546

Middle Eastern (MID)

AF:

0.449

AC:

132

AN:

294

European-Non Finnish (NFE)

AF:

0.406

AC:

27573

AN:

67900

Other (OTH)

AF:

0.442

AC:

932

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1755

3509

5264

7018

8773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.436

Hom.:

6570

Bravo

AF:

0.503

Asia WGS

AF:

0.197

AC:

692

AN:

3478

EpiCase

AF:

0.420

EpiControl

AF:

0.417

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

May 24, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.5

(source)

DANN

Benign

0.66

PhyloP100

-0.25

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000056

dbscSNV1_RF

Benign

0.0

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