11-68312746-C-T

Variant names:

• chr11-68312746-C-T
• rs1282312295
• NM_002335.4:c.32C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2690171).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 23	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.32C>T		non_coding_transcript_exon_variant	Exon 1 of 23	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.00000693 AC: 1 AN: 144332 Hom.: 0 Cov.: 29

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: 7 AN: 916912 Hom.: 0 Cov.: 30 AF XY: 0.00000684 AC XY: 3 AN XY: 438488

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000301

Gnomad4 ASJ exome AF: 0.000246

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000370

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000693 AC: 1 AN: 144332 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 70222

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: 0.0000153

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 11 of the LRP5 protein (p.Pro11Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with LRP5-related conditions. Invitae Evidence 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0082	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	6.3
DANN	Benign	0.92
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.059	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.55	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.20	T
Polyphen		0.98	D
Vest4		0.15
MutPred		0.50		Gain of helix (P = 0.0034);
MVP		0.31
MPC		0.42
ClinPred		0.16	T
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.28

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

Other links and lift over

dbSNP: rs1282312295; hg19: chr11-68080214;