11-68312745-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_002335.4(LRP5):c.31C>T(p.Pro11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000084 in 1,071,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -2.97

Publications

0 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.

PP2

Missense variant in the LRP5 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 71 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 1.6684 (below the threshold of 3.09). Trascript score misZ: 3.6986 (above the threshold of 3.09). GenCC associations: The gene is linked to exudative vitreoretinopathy 4, autosomal dominant osteopetrosis 1, osteoporosis-pseudoglioma syndrome, autosomal dominant osteosclerosis, Worth type, polycystic liver disease 4 with or without kidney cysts, bone mineral density quantitative trait locus 1, osteosclerosis-developmental delay-craniosynostosis syndrome, hyperostosis corticalis generalisata, exudative vitreoretinopathy, polycystic liver disease 1, inherited retinal dystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=0.24055883).

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.31C>T	p.Pro11Ser	missense	Exon 1 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.-1735C>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.31C>T	p.Pro11Ser	missense	Exon 1 of 23	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.31C>T		non_coding_transcript_exon	Exon 1 of 23	ENSP00000436652.1	E9PHY1
LRP5	ENST00000909991.1		c.31C>T	p.Pro11Ser	missense	Exon 1 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.0000348

AC:

AN:

143708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000205

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:

0.0000308

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000452

AC:

AN:

22116

AF XY:

0.0000749

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00140

GnomAD4 exome

AF:

0.00000431

AC:

AN:

927296

Hom.:

Cov.:

AF XY:

0.00000676

AC XY:

AN XY:

443874

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17368

American (AMR)

AF:

0.000140

AC:

AN:

7168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8478

East Asian (EAS)

AF:

0.00

AC:

AN:

5902

South Asian (SAS)

AF:

0.00

AC:

AN:

29862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2010

European-Non Finnish (NFE)

AF:

0.00000244

AC:

AN:

818626

Other (OTH)

AF:

0.0000316

AC:

AN:

31668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000348

AC:

AN:

143708

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

69960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39480

American (AMR)

AF:

0.000205

AC:

AN:

14622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3348

East Asian (EAS)

AF:

0.00

AC:

AN:

4998

South Asian (SAS)

AF:

0.00

AC:

AN:

4754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000308

AC:

AN:

64968

Other (OTH)

AF:

0.00

AC:

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 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

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

CADD

Benign

9.8

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.27

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.34

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.24

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

0.55

PhyloP100

-3.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.40

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Benign

1.0

Polyphen

0.91

Vest4

0.10

MutPred

0.46

Gain of helix (P = 0.027)

MVP

0.31

MPC

0.41

ClinPred

0.067

GERP RS

0.60

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.099

gMVP

0.35

Mutation Taster

=92/8

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over