11-68414907-T-C

Variant names:

• chr11-68414907-T-C
• rs923346
• NM_002335.4:c.2827+895T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002335.4(LRP5):​c.2827+895T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,234 control chromosomes in the GnomAD database, including 1,456 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1456 hom., cov: 33)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 17 publications found

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]

LRP5 Gene-Disease associations (from GenCC):

• bone mineral density quantitative trait locus 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• exudative vitreoretinopathy 4

  Inheritance: AD, SD, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• osteoporosis-pseudoglioma syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant osteosclerosis, Worth type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• polycystic liver disease 4 with or without kidney cysts

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant osteopetrosis 1

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• exudative vitreoretinopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyperostosis corticalis generalisata

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteosclerosis-developmental delay-craniosynostosis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• polycystic liver disease 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.2827+895T>C		intron_variant	Intron 12 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.2827+895T>C		intron_variant	Intron 12 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*1433+895T>C		intron_variant	Intron 12 of 22	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19425 AN: 152116 Hom.: 1455 Cov.: 33

Gnomad AFR AF: 0.0777

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.0841

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.149

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.128 AC: 19441 AN: 152234 Hom.: 1456 Cov.: 33 AF XY: 0.122 AC XY: 9093 AN XY: 74436

African (AFR) AF: 0.0778 AC: 3233 AN: 41550

American (AMR) AF: 0.164 AC: 2504 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3470

East Asian (EAS) AF: 0.200 AC: 1032 AN: 5160

South Asian (SAS) AF: 0.0844 AC: 407 AN: 4822

European-Finnish (FIN) AF: 0.0433 AC: 460 AN: 10622

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10529 AN: 68000

Other (OTH) AF: 0.149 AC: 315 AN: 2112

Alfa AF: 0.150 Hom.: 3011

Bravo AF: 0.142

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.61
PhyloP100		0.020
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs923346; hg19: chr11-68182375;