chr11-68312746-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001291902.2(LRP5):c.-1734C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,061,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

LRP5
NM_001291902.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.04

Publications

1 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: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2690171).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291902.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP5	NM_002335.4	MANE Select	c.32C>T	p.Pro11Leu	missense	Exon 1 of 23	NP_002326.2	O75197
LRP5	NM_001291902.2		c.-1734C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_001278831.1
LRP5	NM_001291902.2		c.-1734C>T		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.32C>T	p.Pro11Leu	missense	Exon 1 of 23	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.32C>T		non_coding_transcript_exon	Exon 1 of 23	ENSP00000436652.1	E9PHY1
LRP5	ENST00000909991.1		c.32C>T	p.Pro11Leu	missense	Exon 1 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.00000693

AC:

AN:

144332

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000763

AC:

AN:

916912

Hom.:

Cov.:

AF XY:

0.00000684

AC XY:

AN XY:

438488

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

17012

American (AMR)

AF:

0.000301

AC:

AN:

6652

Ashkenazi Jewish (ASJ)

AF:

0.000246

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.246

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:

0.00

AC XY:

AN XY:

70222

show subpopulations

African (AFR)

AF:

0.00

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:

0.0000153

AC:

AN:

65194

Other (OTH)

AF:

0.00

AC:

AN:

1998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

0.0082

BayesDel_noAF

Benign

-0.23

CADD

Benign

6.3

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.27

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.0090

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.27

MetaSVM

Uncertain

-0.059

MutationAssessor

Benign

0.55

PhyloP100

-2.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.55

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Benign

0.20

Polyphen

0.98

Vest4

0.15

MutPred

0.50

Gain of helix (P = 0.0034)

MVP

0.31

MPC

0.42

ClinPred

0.16

GERP RS

0.60

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.28

Mutation Taster

=93/7

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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