chr11-68365263-A-G

Variant names:

• chr11-68365263-A-G
• rs314775
• NM_002335.4:c.884-308A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002335.4(LRP5):​c.884-308A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 106,578 control chromosomes in the GnomAD database, including 19,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.68 (19492 hom., cov: 29)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.271
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 11-68365263-A-G is Benign according to our data. Variant chr11-68365263-A-G is described in ClinVar as Benign. ClinVar VariationId is 1262200.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.774 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.884-308A>G		intron	N/A	NP_002326.2
	LRP5	NM_001291902.2		c.-882-308A>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.884-308A>G		intron	N/A	ENSP00000294304.6
	LRP5	ENST00000529993.5	TSL:1	n.884-308A>G		intron	N/A	ENSP00000436652.1
	LRP5	ENST00000909991.1		c.884-308A>G		intron	N/A	ENSP00000580050.1

Frequencies

GnomAD3 genomes AF: 0.677 AC: 72130 AN: 106476 Hom.: 19445 Cov.: 29

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.650

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

GnomAD4 genome AF: 0.678 AC: 72226 AN: 106578 Hom.: 19492 Cov.: 29 AF XY: 0.676 AC XY: 34403 AN XY: 50876

African (AFR) AF: 0.782 AC: 29854 AN: 38190

American (AMR) AF: 0.664 AC: 7619 AN: 11466

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 1347 AN: 2202

East Asian (EAS) AF: 0.475 AC: 572 AN: 1204

South Asian (SAS) AF: 0.537 AC: 836 AN: 1556

European-Finnish (FIN) AF: 0.559 AC: 2745 AN: 4914

Middle Eastern (MID) AF: 0.623 AC: 132 AN: 212

European-Non Finnish (NFE) AF: 0.619 AC: 27588 AN: 44560

Other (OTH) AF: 0.650 AC: 950 AN: 1462

Alfa AF: 0.442 Hom.: 2017

Bravo AF: 0.513

Asia WGS AF: 0.205 AC: 704 AN: 3410

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.5
DANN	Benign	0.58
PhyloP100		-0.27
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: rs314775; hg19: chr11-68132731;