chr11-68410146-T-C

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.2318+6T>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 0.0676 in 1,611,592 control chromosomes in the GnomAD database, including 3,926 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 0.064 ( 371 hom., cov: 31)

Exomes 𝑓: 0.068 ( 3555 hom. )

Consequence

LRP5
NM_002335.4 splice_region, intron

Scores

Splicing: ADA: 0.001634

Clinical Significance

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

Conservation

PhyloP100: -1.41

Publications

11 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=-0.84).

BP6

Variant 11-68410146-T-C is Benign according to our data. Variant chr11-68410146-T-C is described in ClinVar as Benign. ClinVar VariationId is 258636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0691 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.2318+6T>C		splice_region intron	N/A	NP_002326.2
	LRP5	NM_001291902.2		c.575+6T>C		splice_region intron	N/A	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.2318+6T>C	splice_region intron	N/A	ENSP00000294304.6
LRP5	ENST00000529993.5	TSL:1	n.*924+6T>C	splice_region intron	N/A	ENSP00000436652.1
LRP5	ENST00000528714.1	TSL:3	n.112+6T>C	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0635

AC:

9659

AN:

152112

Hom.:

370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0642

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0584

Gnomad ASJ

AF:

0.0496

Gnomad EAS

AF:

0.0439

Gnomad SAS

AF:

0.0406

Gnomad FIN

AF:

0.0452

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.0707

Gnomad OTH

AF:

0.0703

GnomAD2 exomes

AF:

0.0585

AC:

14432

AN:

246616

AF XY:

0.0588

show subpopulations

Gnomad AFR exome

AF:

0.0671

Gnomad AMR exome

AF:

0.0448

Gnomad ASJ exome

AF:

0.0490

Gnomad EAS exome

AF:

0.0409

Gnomad FIN exome

AF:

0.0452

Gnomad NFE exome

AF:

0.0731

Gnomad OTH exome

AF:

0.0677

GnomAD4 exome

AF:

0.0681

AC:

99338

AN:

1459362

Hom.:

3555

Cov.:

AF XY:

0.0672

AC XY:

48768

AN XY:

726062

show subpopulations

African (AFR)

AF:

0.0666

AC:

2226

AN:

33438

American (AMR)

AF:

0.0466

AC:

2077

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.0475

AC:

1239

AN:

26104

East Asian (EAS)

AF:

0.0411

AC:

1630

AN:

39652

South Asian (SAS)

AF:

0.0376

AC:

3237

AN:

86172

European-Finnish (FIN)

AF:

0.0446

AC:

2356

AN:

52874

Middle Eastern (MID)

AF:

0.122

AC:

704

AN:

5750

European-Non Finnish (NFE)

AF:

0.0735

AC:

81611

AN:

1110464

Other (OTH)

AF:

0.0706

AC:

4258

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

4890

9779

14669

19558

24448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2980

5960

8940

11920

14900

<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:

0.0635

AC:

9669

AN:

152230

Hom.:

371

Cov.:

AF XY:

0.0618

AC XY:

4602

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0643

AC:

2669

AN:

41536

American (AMR)

AF:

0.0583

AC:

891

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0496

AC:

172

AN:

3468

East Asian (EAS)

AF:

0.0436

AC:

225

AN:

5164

South Asian (SAS)

AF:

0.0408

AC:

197

AN:

4824

European-Finnish (FIN)

AF:

0.0452

AC:

479

AN:

10606

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0707

AC:

4812

AN:

68018

Other (OTH)

AF:

0.0705

AC:

149

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

469

938

1408

1877

2346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0654

Hom.:

265

Bravo

AF:

0.0665

Asia WGS

AF:

0.0720

AC:

251

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

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:3

Mar 03, 2015

GeneDx

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.6

(source)

DANN

Benign

0.39

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.038

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