11-68348296-C-T

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.488+53C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,593,926 control chromosomes in the GnomAD database, including 139,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 18745 hom., cov: 34)

Exomes 𝑓: 0.40 ( 120335 hom. )

Consequence

LRP5
NM_002335.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.529

Publications

7 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=-0.94).

BP6

Variant 11-68348296-C-T is Benign according to our data. Variant chr11-68348296-C-T is described in ClinVar as Benign. ClinVar VariationId is 1246014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.488+53C>T		intron_variant	Intron 2 of 22	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 link	c.488+53C>T		intron_variant	Intron 2 of 22	1	NM_002335.4	ENSP00000294304.6		O75197
LRP5	ENST00000529993.5 link	n.488+53C>T		intron_variant	Intron 2 of 22	1		ENSP00000436652.1		E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

71136

AN:

152078

Hom.:

18710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.695

Gnomad AMI

AF:

0.640

Gnomad AMR

AF:

0.495

Gnomad ASJ

AF:

0.387

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.406

Gnomad OTH

AF:

0.447

GnomAD4 exome

AF:

0.396

AC:

571179

AN:

1441730

Hom.:

120335

AF XY:

0.388

AC XY:

278129

AN XY:

717318

show subpopulations

African (AFR)

AF:

0.713

AC:

23784

AN:

33376

American (AMR)

AF:

0.530

AC:

23638

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

10129

AN:

26076

East Asian (EAS)

AF:

0.0941

AC:

3725

AN:

39594

South Asian (SAS)

AF:

0.174

AC:

14957

AN:

86114

European-Finnish (FIN)

AF:

0.281

AC:

10915

AN:

38850

Middle Eastern (MID)

AF:

0.445

AC:

2551

AN:

5734

European-Non Finnish (NFE)

AF:

0.413

AC:

457350

AN:

1107272

Other (OTH)

AF:

0.402

AC:

24130

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

17579

35158

52737

70316

87895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14060

28120

42180

56240

70300

<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:

71217

AN:

152196

Hom.:

18745

Cov.:

AF XY:

0.456

AC XY:

33960

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.695

AC:

28857

AN:

41526

American (AMR)

AF:

0.495

AC:

7572

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.387

AC:

1345

AN:

3472

East Asian (EAS)

AF:

0.111

AC:

575

AN:

5176

South Asian (SAS)

AF:

0.175

AC:

843

AN:

4822

European-Finnish (FIN)

AF:

0.260

AC:

2760

AN:

10598

Middle Eastern (MID)

AF:

0.452

AC:

132

AN:

292

European-Non Finnish (NFE)

AF:

0.406

AC:

27615

AN:

67990

Other (OTH)

AF:

0.443

AC:

934

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1803

3607

5410

7214

9017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<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:

0.446

Hom.:

2162

Bravo

AF:

0.504

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.93

(source)

DANN

Benign

0.53

PhyloP100

-0.53

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over