chr11-68427636-C-T

Variant names:

• chr11-68427636-C-T
• rs525592
• NM_002335.4:c.3637+1449C>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.3637+1449C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 151,588 control chromosomes in the GnomAD database, including 10,587 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 0.35 (10587 hom., cov: 31)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.01
• Publications: 16 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
• LRP5-related exudative vitreoretinopathy

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• exudative vitreoretinopathy 4

  Inheritance: Unknown, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• autosomal dominant osteosclerosis, Worth type

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

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

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• 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=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002335.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.3637+1449C>T		intron	N/A	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.1894+1449C>T		intron	N/A	NP_001278831.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	ENST00000294304.12	TSL:1 MANE Select	c.3637+1449C>T		intron	N/A	ENSP00000294304.6	O75197
	LRP5	ENST00000529993.5	TSL:1	n.*2243+1449C>T		intron	N/A	ENSP00000436652.1	E9PHY1
	LRP5	ENST00000909991.1		c.3700+1449C>T		intron	N/A	ENSP00000580050.1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53574 AN: 151468 Hom.: 10561 Cov.: 31

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.364

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

GnomAD4 genome AF: 0.354 AC: 53646 AN: 151588 Hom.: 10587 Cov.: 31 AF XY: 0.342 AC XY: 25308 AN XY: 74054

African (AFR) AF: 0.510 AC: 21019 AN: 41244

American (AMR) AF: 0.329 AC: 5016 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1037 AN: 3468

East Asian (EAS) AF: 0.266 AC: 1372 AN: 5150

South Asian (SAS) AF: 0.201 AC: 968 AN: 4804

European-Finnish (FIN) AF: 0.125 AC: 1307 AN: 10468

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21517 AN: 67908

Other (OTH) AF: 0.363 AC: 764 AN: 2106

Alfa AF: 0.172 Hom.: 340

Bravo AF: 0.383

Asia WGS AF: 0.273 AC: 952 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.49
PhyloP100		-3.0
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: rs525592; hg19: chr11-68195104;