rs901824

Variant names:

• chr11-68438705-T-C
• rs901824
• NM_002335.4:c.4348+23T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002335.4(LRP5):​c.4348+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,602,452 control chromosomes in the GnomAD database, including 6,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (881 hom., cov: 33)
  • Exomes 𝑓: 0.085 (5557 hom.)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.60
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-68438705-T-C is Benign according to our data. Variant chr11-68438705-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.4348+23T>C		intron_variant	Intron 20 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.4348+23T>C		intron_variant	Intron 20 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*2954+23T>C		intron_variant	Intron 20 of 22	1		ENSP00000436652.1
LRP5	ENST00000533695.1	n.90+23T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 14944 AN: 152176 Hom.: 880 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.0744

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.0434

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0502

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0868

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.0749 AC: 18122 AN: 242098 AF XY: 0.0740

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.0547

Gnomad ASJ exome AF: 0.0890

Gnomad EAS exome AF: 0.0382

Gnomad FIN exome AF: 0.0501

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0813

GnomAD4 exome AF: 0.0849 AC: 123106 AN: 1450158 Hom.: 5557 Cov.: 30 AF XY: 0.0835 AC XY: 60256 AN XY: 721952

African (AFR) AF: 0.153 AC: 5114 AN: 33340

American (AMR) AF: 0.0581 AC: 2593 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 2329 AN: 26062

East Asian (EAS) AF: 0.0455 AC: 1806 AN: 39650

South Asian (SAS) AF: 0.0395 AC: 3398 AN: 86084

European-Finnish (FIN) AF: 0.0490 AC: 2366 AN: 48272

Middle Eastern (MID) AF: 0.135 AC: 754 AN: 5598

European-Non Finnish (NFE) AF: 0.0897 AC: 99259 AN: 1106414

Other (OTH) AF: 0.0913 AC: 5487 AN: 60118

GnomAD4 genome AF: 0.0982 AC: 14956 AN: 152294 Hom.: 881 Cov.: 33 AF XY: 0.0949 AC XY: 7068 AN XY: 74464

African (AFR) AF: 0.148 AC: 6159 AN: 41550

American (AMR) AF: 0.0742 AC: 1135 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3472

East Asian (EAS) AF: 0.0433 AC: 224 AN: 5178

South Asian (SAS) AF: 0.0449 AC: 217 AN: 4828

European-Finnish (FIN) AF: 0.0502 AC: 533 AN: 10622

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0868 AC: 5908 AN: 68026

Other (OTH) AF: 0.103 AC: 218 AN: 2114

Alfa AF: 0.0918 Hom.: 471

Bravo AF: 0.105

Asia WGS AF: 0.0750 AC: 263 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.37
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs901824; hg19: chr11-68206173;