rs80358306

Positions:

chr11-68357679-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001291902.2(LRP5):c.-1248C>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 0.000253 in 1,614,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

LRP5
NM_001291902.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: -0.110

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:

LRP5 (HGNC:):

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.518C>T	p.Thr173Met	missense_variant	3/23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 linkuse as main transcript	c.518C>T	p.Thr173Met	missense_variant	3/23	1	NM_002335.4	ENSP00000294304.6		O75197
LRP5	ENST00000529993.5 linkuse as main transcript	n.518C>T		non_coding_transcript_exon_variant	3/23	1		ENSP00000436652.1		E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000391

AC:

AN:

250806

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00125

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000225

AC:

329

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

163

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.000765

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.000510

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000525

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000438

Hom.:

Bravo

AF:

0.000450

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000371

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2020	Reported previously in association with familial exudative vitreoretinopathy, but the variant was inherited from an unaffected parent (Toomes et al., 2004; Li et al., 2018); Published functional studies demonstrate no damaging effect (Ai et al., 2005); This variant is associated with the following publications: (PMID: 22995991, 15923613, 16252235, 26348019, 15024691, 20340138, 24715757, 30452590) -

LRP5-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The LRP5 c.518C>T variant is predicted to result in the amino acid substitution p.Thr173Met. This variant has been reported in two individuals with familial exudative vitreoretinopathy (Toomes et al. 2004. PubMed ID: 15024691; Li et al. 2018. PubMed ID: 30452590), and in an individual with high bone mass (Gregson et al. 2015. PubMed ID: 26348019). However, this variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD, including 1 homozygous individual in the newest dataset (https://gnomad.broadinstitute.org/variant/11-68357679-C-T?dataset=gnomad_r4). Therefore, although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

0.92

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.41

REVEL

Uncertain

0.61

Sift

Benign

0.11

Sift4G

Benign

0.23

Polyphen

0.98

Vest4

0.71

MVP

0.83

MPC

0.54

ClinPred

0.013

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.46

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