11-68312746-C-CGCT

Position:

• chr11-68312746-C-CGCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002335.4(LRP5):​c.58_60dup​(p.Leu20dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 1,060,778 control chromosomes in the GnomAD database, including 2,064 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (821 hom., cov: 28)
  • Exomes 𝑓: 0.080 (1243 hom.)
• Consequence: LRP5 NM_002335.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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 Benign. Variant got -16 ACMG points.

• BP6: Variant 11-68312746-C-CGCT is Benign according to our data. Variant chr11-68312746-C-CGCT is described in ClinVar as [Likely_benign]. Clinvar id is 193231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.58_60dup	p.Leu20dup	inframe_insertion	1/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.58_60dup	p.Leu20dup	inframe_insertion	1/23	1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5	c.58_60dup	p.Leu20dup	inframe_insertion, NMD_transcript_variant	1/23	1		ENSP00000436652

Frequencies

GnomAD3 genomes AF: 0.101 AC: 14633 AN: 144284 Hom.: 819 Cov.: 28

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0125

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0178

Gnomad SAS AF: 0.0729

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.0839

Gnomad OTH AF: 0.0866

GnomAD3 exomes AF: 0.0724 AC: 1181 AN: 16308 Hom.: 25 AF XY: 0.0727 AC XY: 717 AN XY: 9856

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0152

Gnomad SAS exome AF: 0.0604

Gnomad FIN exome AF: 0.0984

Gnomad NFE exome AF: 0.0752

Gnomad OTH exome AF: 0.0913

GnomAD4 exome AF: 0.0805 AC: 73751 AN: 916408 Hom.: 1243 Cov.: 5 AF XY: 0.0807 AC XY: 35351 AN XY: 438204

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.0528

Gnomad4 ASJ exome AF: 0.0949

Gnomad4 EAS exome AF: 0.0151

Gnomad4 SAS exome AF: 0.0660

Gnomad4 FIN exome AF: 0.0957

Gnomad4 NFE exome AF: 0.0796

Gnomad4 OTH exome AF: 0.0811

GnomAD4 genome AF: 0.101 AC: 14647 AN: 144370 Hom.: 821 Cov.: 28 AF XY: 0.101 AC XY: 7085 AN XY: 70296

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.0695

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.0177

Gnomad4 SAS AF: 0.0733

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0839

Gnomad4 OTH AF: 0.0863

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Osteoporosis with pseudoglioma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of osteoporosis-pseudoglioma syndrome (MIM#259770), with 791 homozygotes in gnomAD v3. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Exudative vitreoretinopathy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

African/African American population allele frequency is 13.45% (rs564221347, 1220/7934 alleles, 89 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

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;