rs576118

Variant names:

• chr11-68410240-G-A
• rs576118
• NM_002335.4:c.2318+100G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-68410240-G-A
• chr11-68410240-G-C
• chr11-68410240-G-T

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.2318+100G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 933,354 control chromosomes in the GnomAD database, including 266,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38384 hom., cov: 32)
  • Exomes 𝑓: 0.76 (228526 hom.)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.44
• Publications: 15 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=-0.91).
• BP6: Variant 11-68410240-G-A is Benign according to our data. Variant chr11-68410240-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.2318+100G>A		intron_variant	Intron 10 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.2318+100G>A		intron_variant	Intron 10 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*924+100G>A		intron_variant	Intron 10 of 22	1		ENSP00000436652.1
LRP5	ENST00000528714.1	n.112+100G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106042 AN: 151968 Hom.: 38379 Cov.: 32

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.692

GnomAD4 exome AF: 0.762 AC: 595480 AN: 781268 Hom.: 228526 AF XY: 0.767 AC XY: 312908 AN XY: 408172

African (AFR) AF: 0.505 AC: 10110 AN: 20026

American (AMR) AF: 0.738 AC: 25885 AN: 35090

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 15752 AN: 21342

East Asian (EAS) AF: 0.736 AC: 24324 AN: 33048

South Asian (SAS) AF: 0.836 AC: 55742 AN: 66700

European-Finnish (FIN) AF: 0.913 AC: 41241 AN: 45152

Middle Eastern (MID) AF: 0.740 AC: 2304 AN: 3114

European-Non Finnish (NFE) AF: 0.755 AC: 392064 AN: 519124

Other (OTH) AF: 0.745 AC: 28058 AN: 37672

GnomAD4 genome AF: 0.697 AC: 106078 AN: 152086 Hom.: 38384 Cov.: 32 AF XY: 0.709 AC XY: 52727 AN XY: 74346

African (AFR) AF: 0.507 AC: 20999 AN: 41438

American (AMR) AF: 0.719 AC: 10991 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2607 AN: 3468

East Asian (EAS) AF: 0.782 AC: 4040 AN: 5164

South Asian (SAS) AF: 0.840 AC: 4056 AN: 4826

European-Finnish (FIN) AF: 0.927 AC: 9823 AN: 10600

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.757 AC: 51479 AN: 67992

Other (OTH) AF: 0.693 AC: 1463 AN: 2110

Alfa AF: 0.731 Hom.: 47829

Bravo AF: 0.667

Asia WGS AF: 0.789 AC: 2742 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.10
DANN	Benign	0.53
PhyloP100		-3.4
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: rs576118; hg19: chr11-68177708;