11-68312746-CGCTGCTGCTGCTGCT-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002335.4(LRP5):c.46_60delCTGCTGCTGCTGCTG(p.Leu16_Leu20del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,061,244 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Consequence

LRP5
NM_002335.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.307

Publications

4 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: Uncertain_significance. The variant received 0 ACMG points.

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.46_60delCTGCTGCTGCTGCTG	p.Leu16_Leu20del	conservative_inframe_deletion	Exon 1 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.-1720_-1706delCTGCTGCTGCTGCTG		5_prime_UTR	Exon 1 of 23	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.46_60delCTGCTGCTGCTGCTG	p.Leu16_Leu20del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.46_60delCTGCTGCTGCTGCTG		non_coding_transcript_exon	Exon 1 of 23	ENSP00000436652.1	E9PHY1
LRP5	ENST00000909991.1		c.46_60delCTGCTGCTGCTGCTG	p.Leu16_Leu20del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.00000693

AC:

AN:

144332

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000327

AC:

AN:

916912

Hom.:

AF XY:

0.00

AC XY:

AN XY:

438488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17012

American (AMR)

AF:

0.00

AC:

AN:

6652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8138

East Asian (EAS)

AF:

0.00

AC:

AN:

5840

South Asian (SAS)

AF:

0.00

AC:

AN:

28828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1966

European-Non Finnish (NFE)

AF:

0.00000370

AC:

AN:

811342

Other (OTH)

AF:

0.00

AC:

AN:

31264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000693

AC:

AN:

144332

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

70222

show subpopulations

African (AFR)

AF:

0.0000251

AC:

AN:

39912

American (AMR)

AF:

0.00

AC:

AN:

14634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3366

East Asian (EAS)

AF:

0.00

AC:

AN:

4942

South Asian (SAS)

AF:

0.00

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65194

Other (OTH)

AF:

0.00

AC:

AN:

1998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Osteoporosis;C0432252:Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 1;C1851402:Exudative vitreoretinopathy 1;C1866079:Bone mineral density quantitative trait locus 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.31

Mutation Taster

=101/99

polymorphism

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over