rs373910016

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_002335.4(LRP5):c.1360G>A(p.Val454Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2O:1

Conservation

PhyloP100: 6.20

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002335.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, LRP5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.1360G>A	p.Val454Met	missense_variant	6/23	ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12 linkuse as main transcript	c.1360G>A	p.Val454Met	missense_variant	6/23	1	NM_002335.4	P1
LRP5	ENST00000529993.5 linkuse as main transcript	c.1360G>A	p.Val454Met	missense_variant, NMD_transcript_variant	6/23	1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152234

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249710

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135224

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461232

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic liver disease 4 with or without kidney cysts

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 08, 2014

- -

Osteogenesis imperfecta

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 31, 2019

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRP5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 183258). This missense change has been observed in individual(s) with polycystic liver disease (PMID: 24706814). This variant is present in population databases (rs373910016, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 454 of the LRP5 protein (p.Val454Met). -

Polycystic liver disease 1

Other:1

not provided, no classification provided

not provided

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.94

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0050

Polyphen

0.87

Vest4

0.81

MVP

0.67

MPC

0.95

ClinPred

0.82

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.13

gMVP

0.63

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