11-68312746-CGCTGCTGCTGCTGCT-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Position:

• chr11-68312746-CGCTGCTGCTGCTGCT-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002335.4(LRP5):​c.46_60dup​(p.Leu16_Leu20dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRP5 NM_002335.4 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.46_60dup	p.Leu16_Leu20dup	inframe_insertion	1/23	ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.46_60dup	p.Leu16_Leu20dup	inframe_insertion	1/23	1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.46_60dup	p.Leu16_Leu20dup	inframe_insertion, NMD_transcript_variant	1/23	1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000218 AC: 2 AN: 916916 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 438490

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: 0.00000123

Gnomad4 OTH exome AF: 0.0000320

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2021

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with LRP5-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant, c.46_60dup, results in the insertion of 5 amino acid(s) to the LRP5 protein (p.Leu16_Leu20dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-68080214;