rs11602256

Variant names:

• chr11-68376815-C-T
• rs11602256
• NM_002335.4:c.1016-9501C>T

Variant summary

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

The NM_002335.4(LRP5):​c.1016-9501C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,104 control chromosomes in the GnomAD database, including 9,378 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 0.34 (9378 hom., cov: 33)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.677
• Publications: 11 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.1016-9501C>T		intron_variant	Intron 5 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.1016-9501C>T		intron_variant	Intron 5 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.1016-9501C>T		intron_variant	Intron 5 of 22	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51661 AN: 151986 Hom.: 9360 Cov.: 33

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.394

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.344

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

GnomAD4 genome AF: 0.340 AC: 51717 AN: 152104 Hom.: 9378 Cov.: 33 AF XY: 0.329 AC XY: 24431 AN XY: 74348

African (AFR) AF: 0.420 AC: 17391 AN: 41446

American (AMR) AF: 0.425 AC: 6494 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1101 AN: 3470

East Asian (EAS) AF: 0.124 AC: 644 AN: 5176

South Asian (SAS) AF: 0.117 AC: 562 AN: 4818

European-Finnish (FIN) AF: 0.171 AC: 1808 AN: 10600

Middle Eastern (MID) AF: 0.400 AC: 116 AN: 290

European-Non Finnish (NFE) AF: 0.329 AC: 22349 AN: 67992

Other (OTH) AF: 0.341 AC: 721 AN: 2112

Alfa AF: 0.326 Hom.: 4431

Bravo AF: 0.373

Asia WGS AF: 0.149 AC: 520 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.73
DANN	Benign	0.49
PhyloP100		-0.68
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: rs11602256; hg19: chr11-68144283;