11-68403545-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002335.4(LRP5):c.1647T>C(p.Phe549Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 1,614,072 control chromosomes in the GnomAD database, including 659,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 54985 hom., cov: 32)

Exomes 𝑓: 0.91 ( 604642 hom. )

Consequence

LRP5
NM_002335.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0750

Publications

47 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 11-68403545-T-C is Benign according to our data. Variant chr11-68403545-T-C is described in ClinVar as Benign. ClinVar VariationId is 258634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.075 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002335.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.1647T>C	p.Phe549Phe	synonymous	Exon 8 of 23	NP_002326.2
	LRP5	NM_001291902.2		c.-291T>C		5_prime_UTR	Exon 7 of 23	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.1647T>C	p.Phe549Phe	synonymous	Exon 8 of 23	ENSP00000294304.6
LRP5	ENST00000529993.5	TSL:1	n.*59T>C		non_coding_transcript_exon	Exon 7 of 23	ENSP00000436652.1
LRP5	ENST00000529993.5	TSL:1	n.*59T>C		3_prime_UTR	Exon 7 of 23	ENSP00000436652.1

Frequencies

GnomAD3 genomes

AF:

0.840

AC:

127718

AN:

152124

Hom.:

54955

Cov.:

show subpopulations

Gnomad AFR

AF:

0.633

Gnomad AMI

AF:

0.924

Gnomad AMR

AF:

0.889

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.927

Gnomad FIN

AF:

0.970

Gnomad MID

AF:

0.848

Gnomad NFE

AF:

0.912

Gnomad OTH

AF:

0.848

GnomAD2 exomes

AF:

0.906

AC:

227863

AN:

251440

AF XY:

0.911

show subpopulations

Gnomad AFR exome

AF:

0.625

Gnomad AMR exome

AF:

0.936

Gnomad ASJ exome

AF:

0.890

Gnomad EAS exome

AF:

0.989

Gnomad FIN exome

AF:

0.964

Gnomad NFE exome

AF:

0.910

Gnomad OTH exome

AF:

0.903

GnomAD4 exome

AF:

0.908

AC:

1327694

AN:

1461830

Hom.:

604642

Cov.:

AF XY:

0.910

AC XY:

661464

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.625

AC:

20928

AN:

33480

American (AMR)

AF:

0.932

AC:

41678

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.892

AC:

23313

AN:

26136

East Asian (EAS)

AF:

0.976

AC:

38753

AN:

39698

South Asian (SAS)

AF:

0.920

AC:

79373

AN:

86258

European-Finnish (FIN)

AF:

0.962

AC:

51383

AN:

53388

Middle Eastern (MID)

AF:

0.855

AC:

4929

AN:

5768

European-Non Finnish (NFE)

AF:

0.911

AC:

1013430

AN:

1111986

Other (OTH)

AF:

0.893

AC:

53907

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

7611

15222

22833

30444

38055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21474

42948

64422

85896

107370

<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:

0.839

AC:

127799

AN:

152242

Hom.:

54985

Cov.:

AF XY:

0.845

AC XY:

62913

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.633

AC:

26281

AN:

41506

American (AMR)

AF:

0.889

AC:

13609

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

3104

AN:

3470

East Asian (EAS)

AF:

0.984

AC:

5089

AN:

5172

South Asian (SAS)

AF:

0.927

AC:

4474

AN:

4826

European-Finnish (FIN)

AF:

0.970

AC:

10307

AN:

10622

Middle Eastern (MID)

AF:

0.844

AC:

248

AN:

294

European-Non Finnish (NFE)

AF:

0.912

AC:

62049

AN:

68026

Other (OTH)

AF:

0.849

AC:

1795

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

940

1881

2821

3762

4702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

878

1756

2634

3512

4390

<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:

0.887

Hom.:

132401

Bravo

AF:

0.825

Asia WGS

AF:

0.926

AC:

3219

AN:

3478

EpiCase

AF:

0.908

EpiControl

AF:

0.908

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

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: 30747064)

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

2.2

(source)

DANN

Benign

0.61

PhyloP100

-0.075

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over