rs148685646

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002335.4(LRP5):c.4000+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,610,128 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 31 hom. )

Consequence

LRP5
NM_002335.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.348

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 11-68433847-C-T is Benign according to our data. Variant chr11-68433847-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68433847-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.004 (610/152336) while in subpopulation NFE AF= 0.00548 (373/68026). AF 95% confidence interval is 0.00502. There are 3 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.4000+9C>T		intron_variant	Intron 18 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.4000+9C>T		intron_variant	Intron 18 of 22	1	NM_002335.4	ENSP00000294304.6		O75197
LRP5	ENST00000529993.5 link	n.*2606+9C>T		intron_variant	Intron 18 of 22	1		ENSP00000436652.1		E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.00400

AC:

609

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00548

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00524

AC:

1246

AN:

237960

Hom.:

AF XY:

0.00535

AC XY:

699

AN XY:

130606

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.00458

Gnomad ASJ exome

AF:

0.0305

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00433

Gnomad FIN exome

AF:

0.000196

Gnomad NFE exome

AF:

0.00550

Gnomad OTH exome

AF:

0.00970

GnomAD4 exome

AF:

0.00499

AC:

7280

AN:

1457792

Hom.:

Cov.:

AF XY:

0.00507

AC XY:

3676

AN XY:

725252

show subpopulations

Gnomad4 AFR exome

AF:

0.00171

Gnomad4 AMR exome

AF:

0.00465

Gnomad4 ASJ exome

AF:

0.0299

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00402

Gnomad4 FIN exome

AF:

0.000597

Gnomad4 NFE exome

AF:

0.00484

Gnomad4 OTH exome

AF:

0.00625

GnomAD4 genome

AF:

0.00400

AC:

610

AN:

152336

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

303

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00538

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00548

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00717

Hom.:

Bravo

AF:

0.00427

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LRP5: BS2 -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:4

Nov 07, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LRP5 c.4000+9C>T alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing (TrAP). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0052 in 237960 control chromosomes, predominantly at a frequency of 0.0055 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 41.064 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP5 causing Idiopathic Osteoporosis phenotype (0.00013). To our knowledge, no occurrence of c.4000+9C>T in individuals affected with Idiopathic Osteoporosis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 36481). Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta

Benign:1

May 13, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Increased bone mineral density

Benign:1

May 13, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

-0.67

CADD

Benign

9.4

DANN

Benign

0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over