11-68312746-CGCTGCTGCT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002335.4(LRP5):c.52_60del(p.Leu18_Leu20del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,061,146 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (5 hom., cov: 28)
  • Exomes 𝑓: 0.014 (70 hom.)
• Consequence: LRP5 NM_002335.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 0.190

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 11-68312746-CGCTGCTGCT-C is Benign according to our data. Variant chr11-68312746-CGCTGCTGCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 204504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68312746-CGCTGCTGCT-C is described in Lovd as [Benign]. Variant chr11-68312746-CGCTGCTGCT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00902 (1303/144404) while in subpopulation NFE AF= 0.0137 (894/65172). AF 95% confidence interval is 0.013. There are 5 homozygotes in gnomad4. There are 584 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.52_60del	p.Leu18_Leu20del	inframe_deletion	1/23	ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.52_60del	p.Leu18_Leu20del	inframe_deletion	1/23	1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.52_60del	p.Leu18_Leu20del	inframe_deletion, NMD_transcript_variant	1/23	1

Frequencies

GnomAD3 genomes AF: 0.00901 AC: 1300 AN: 144318 Hom.: 5 Cov.: 28

Gnomad AFR AF: 0.00371

Gnomad AMI AF: 0.00340

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00446

Gnomad EAS AF: 0.000809

Gnomad SAS AF: 0.00168

Gnomad FIN AF: 0.00383

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00901

GnomAD3 exomes AF: 0.000491 AC: 8 AN: 16308 Hom.: 0 AF XY: 0.000812 AC XY: 8 AN XY: 9856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000681

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: 0.00105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0137 AC: 12529 AN: 916742 Hom.: 70 AF XY: 0.0134 AC XY: 5870 AN XY: 438388

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00361

Gnomad4 ASJ exome AF: 0.00332

Gnomad4 EAS exome AF: 0.000171

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00341

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.00979

GnomAD4 genome AF: 0.00902 AC: 1303 AN: 144404 Hom.: 5 Cov.: 28 AF XY: 0.00831 AC XY: 584 AN XY: 70312

Gnomad4 AFR AF: 0.00377

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.00446

Gnomad4 EAS AF: 0.000812

Gnomad4 SAS AF: 0.00169

Gnomad4 FIN AF: 0.00383

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.00893

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2019	This variant is associated with the following publications: (PMID: 21151595, 12579474, 16234968, 19177549) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LRP5: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Autosomal dominant polycystic liver disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

Osteogenesis imperfecta Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 21, 2022

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 16, 2017

- -

Increased bone mineral density Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 21, 2022

- -

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;