rs11228202

Variant names:

• chr11-68316760-C-T
• rs11228202
• NM_002335.4:c.91+3955C>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.91+3955C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 152,202 control chromosomes in the GnomAD database, including 833 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 0.10 (833 hom., cov: 33)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 5 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

LOC124900302 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.91+3955C>T		intron_variant	Intron 1 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.91+3955C>T		intron_variant	Intron 1 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.91+3955C>T		intron_variant	Intron 1 of 22	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15244 AN: 152084 Hom.: 831 Cov.: 33

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0623

Gnomad EAS AF: 0.0282

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.100 AC: 15254 AN: 152202 Hom.: 833 Cov.: 33 AF XY: 0.0961 AC XY: 7146 AN XY: 74396

African (AFR) AF: 0.0982 AC: 4077 AN: 41524

American (AMR) AF: 0.106 AC: 1617 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 216 AN: 3468

East Asian (EAS) AF: 0.0277 AC: 143 AN: 5170

South Asian (SAS) AF: 0.0398 AC: 192 AN: 4822

European-Finnish (FIN) AF: 0.0445 AC: 472 AN: 10608

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8030 AN: 67998

Other (OTH) AF: 0.115 AC: 243 AN: 2114

Alfa AF: 0.101 Hom.: 104

Bravo AF: 0.106

Asia WGS AF: 0.0630 AC: 217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.70
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs11228202; hg19: chr11-68084228;