rs491347

Variant names:

• chr11-68402220-G-A
• rs491347
• NM_002335.4:c.1585-1263G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-68402220-G-A
• chr11-68402220-G-C
• chr11-68402220-G-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.1585-1263G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 152,024 control chromosomes in the GnomAD database, including 37,290 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 0.68 (37290 hom., cov: 31)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.664
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.1585-1263G>A		intron_variant	Intron 7 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.1585-1263G>A		intron_variant	Intron 7 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.1413-1263G>A		intron_variant	Intron 6 of 22	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103976 AN: 151906 Hom.: 37283 Cov.: 31

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.747

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.674

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

GnomAD4 genome AF: 0.684 AC: 104010 AN: 152024 Hom.: 37290 Cov.: 31 AF XY: 0.696 AC XY: 51771 AN XY: 74340

African (AFR) AF: 0.463 AC: 19171 AN: 41406

American (AMR) AF: 0.714 AC: 10895 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2588 AN: 3464

East Asian (EAS) AF: 0.781 AC: 4030 AN: 5162

South Asian (SAS) AF: 0.838 AC: 4042 AN: 4822

European-Finnish (FIN) AF: 0.927 AC: 9827 AN: 10600

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.756 AC: 51420 AN: 68002

Other (OTH) AF: 0.675 AC: 1423 AN: 2108

Alfa AF: 0.659 Hom.: 2410

Bravo AF: 0.652

Asia WGS AF: 0.786 AC: 2734 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.052
DANN	Benign	0.76
PhyloP100		-0.66
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: rs491347; hg19: chr11-68169688;