11-68312746-CGCTGCT-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_002335.4(LRP5):c.55_60del(p.Leu19_Leu20del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,060,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: LRP5 NM_002335.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B: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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-68312746-CGCTGCT-C is Benign according to our data. Variant chr11-68312746-CGCTGCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr11-68312746-CGCTGCT-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.55_60del	p.Leu19_Leu20del	inframe_deletion	1/23	ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.55_60del	p.Leu19_Leu20del	inframe_deletion	1/23	1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.55_60del	p.Leu19_Leu20del	inframe_deletion, NMD_transcript_variant	1/23	1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 39 AN: 144332 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.000297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.000307

Gnomad OTH AF: 0.00150

GnomAD4 exome AF: 0.000313 AC: 287 AN: 915972 Hom.: 0 AF XY: 0.000327 AC XY: 143 AN XY: 437958

Gnomad4 AFR exome AF: 0.000118

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.000864

Gnomad4 EAS exome AF: 0.000858

Gnomad4 SAS exome AF: 0.000801

Gnomad4 FIN exome AF: 0.000512

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.000384

GnomAD4 genome AF: 0.000270 AC: 39 AN: 144418 Hom.: 0 Cov.: 28 AF XY: 0.000213 AC XY: 15 AN XY: 70314

Gnomad4 AFR AF: 0.000250

Gnomad4 AMR AF: 0.000136

Gnomad4 ASJ AF: 0.000297

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000307

Gnomad4 OTH AF: 0.00149

Bravo AF: 0.000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2016	- -

Osteogenesis imperfecta Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72555376; hg19: chr11-68080214;