chr11-68312730-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_002335.4(LRP5):c.16C>T(p.Pro6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000011 in 907,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.171

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
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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.1582931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.16C>T	p.Pro6Ser	missense_variant	Exon 1 of 23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 link	c.16C>T	p.Pro6Ser	missense_variant	Exon 1 of 23	1	NM_002335.4	ENSP00000294304.6		O75197
LRP5	ENST00000529993.5 link	n.16C>T		non_coding_transcript_exon_variant	Exon 1 of 23	1		ENSP00000436652.1		E9PHY1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000110

AC:

AN:

907496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

432232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16986

American (AMR)

AF:

0.00

AC:

AN:

5284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7438

East Asian (EAS)

AF:

0.00

AC:

AN:

5480

South Asian (SAS)

AF:

0.00

AC:

AN:

26302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1926

European-Non Finnish (NFE)

AF:

0.00000124

AC:

AN:

808490

Other (OTH)

AF:

0.00

AC:

AN:

30694

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.0021

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.27

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.37

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.69

PhyloP100

0.17

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.42

REVEL

Benign

0.25

Sift

Pathogenic

0.0

Polyphen

0.0

Vest4

0.20

MutPred

0.43

Gain of phosphorylation at P6 (P = 0.0514);

MVP

0.44

MPC

0.41

ClinPred

0.070

GERP RS

-1.6

PromoterAI

-0.046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.071

gMVP

0.29

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over