NM_002335.4:c.3237-224T>G

Variant names:

• chr11-68424878-T-G
• rs599083
• NM_002335.4:c.3237-224T>G

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.3237-224T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 152,140 control chromosomes in the GnomAD database, including 9,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.34 (9550 hom., cov: 33)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0210
• Publications: 43 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-68424878-T-G is Benign according to our data. Variant chr11-68424878-T-G is described in ClinVar as Benign. ClinVar VariationId is 1222543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.461 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.3237-224T>G		intron	N/A	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.1494-224T>G		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.3237-224T>G		intron	N/A	ENSP00000294304.6	O75197
	LRP5	ENST00000529993.5	TSL:1	n.*1843-224T>G		intron	N/A	ENSP00000436652.1	E9PHY1
	LRP5	ENST00000909991.1		c.3300-224T>G		intron	N/A	ENSP00000580050.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51248 AN: 152020 Hom.: 9531 Cov.: 33

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.337 AC: 51317 AN: 152140 Hom.: 9550 Cov.: 33 AF XY: 0.325 AC XY: 24188 AN XY: 74372

African (AFR) AF: 0.467 AC: 19365 AN: 41476

American (AMR) AF: 0.317 AC: 4845 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1015 AN: 3468

East Asian (EAS) AF: 0.260 AC: 1342 AN: 5168

South Asian (SAS) AF: 0.199 AC: 962 AN: 4830

European-Finnish (FIN) AF: 0.119 AC: 1264 AN: 10598

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21121 AN: 67978

Other (OTH) AF: 0.350 AC: 740 AN: 2114

Alfa AF: 0.327 Hom.: 24850

Bravo AF: 0.366

Asia WGS AF: 0.269 AC: 938 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.30
PhyloP100		-0.021
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: rs599083; hg19: chr11-68192346;