rs901825

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.4348+47G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,568,886 control chromosomes in the GnomAD database, including 6,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.098 ( 881 hom., cov: 33)

Exomes 𝑓: 0.085 ( 5384 hom. )

Consequence

LRP5
NM_002335.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.219

Publications

5 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
LRP5-related exudative vitreoretinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
osteoporosis-pseudoglioma syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
exudative vitreoretinopathy 4
Inheritance: Unknown, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal dominant osteosclerosis, Worth type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
polycystic liver disease 4 with or without kidney cysts
Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
autosomal dominant osteopetrosis 1
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
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=-0.81).

BP6

Variant 11-68438729-G-C is Benign according to our data. Variant chr11-68438729-G-C is described in ClinVar as Benign. ClinVar VariationId is 1223965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.4348+47G>C		intron	N/A	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.2605+47G>C		intron	N/A	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.4348+47G>C	intron	N/A	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.*2954+47G>C	intron	N/A	ENSP00000436652.1	E9PHY1
LRP5	ENST00000909991.1		c.4411+47G>C	intron	N/A	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.0981

AC:

14931

AN:

152160

Hom.:

880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.215

Gnomad AMR

AF:

0.0744

Gnomad ASJ

AF:

0.0919

Gnomad EAS

AF:

0.0432

Gnomad SAS

AF:

0.0445

Gnomad FIN

AF:

0.0502

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.0867

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.0740

AC:

17342

AN:

234232

AF XY:

0.0732

show subpopulations

Gnomad AFR exome

AF:

0.151

Gnomad AMR exome

AF:

0.0543

Gnomad ASJ exome

AF:

0.0880

Gnomad EAS exome

AF:

0.0382

Gnomad FIN exome

AF:

0.0482

Gnomad NFE exome

AF:

0.0881

Gnomad OTH exome

AF:

0.0812

GnomAD4 exome

AF:

0.0845

AC:

119773

AN:

1416608

Hom.:

5384

Cov.:

AF XY:

0.0831

AC XY:

58727

AN XY:

706888

show subpopulations

African (AFR)

AF:

0.153

AC:

4998

AN:

32744

American (AMR)

AF:

0.0578

AC:

2566

AN:

44406

Ashkenazi Jewish (ASJ)

AF:

0.0889

AC:

2290

AN:

25748

East Asian (EAS)

AF:

0.0456

AC:

1803

AN:

39532

South Asian (SAS)

AF:

0.0393

AC:

3352

AN:

85278

European-Finnish (FIN)

AF:

0.0486

AC:

2087

AN:

42914

Middle Eastern (MID)

AF:

0.133

AC:

701

AN:

5284

European-Non Finnish (NFE)

AF:

0.0893

AC:

96590

AN:

1081542

Other (OTH)

AF:

0.0910

AC:

5386

AN:

59160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

5596

11192

16788

22384

27980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3520

7040

10560

14080

17600

<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:

0.0981

AC:

14943

AN:

152278

Hom.:

881

Cov.:

AF XY:

0.0948

AC XY:

7058

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.148

AC:

6154

AN:

41552

American (AMR)

AF:

0.0742

AC:

1136

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0919

AC:

319

AN:

3472

East Asian (EAS)

AF:

0.0432

AC:

223

AN:

5168

South Asian (SAS)

AF:

0.0447

AC:

216

AN:

4828

European-Finnish (FIN)

AF:

0.0502

AC:

533

AN:

10614

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0868

AC:

5903

AN:

68020

Other (OTH)

AF:

0.103

AC:

218

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

700

1400

2100

2800

3500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0893

Hom.:

134

Bravo

AF:

0.105

Asia WGS

AF:

0.0750

AC:

262

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.9

(source)

DANN

Benign

0.35

PhyloP100

-0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over