11-68333888-C-T

Variant names:

• chr11-68333888-C-T
• rs7944040
• NM_002335.4:c.92-13959C>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.92-13959C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 151,922 control chromosomes in the GnomAD database, including 21,739 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 0.51 (21739 hom., cov: 31)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• 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

ENSG00000300058 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.92-13959C>T		intron_variant	Intron 1 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.92-13959C>T		intron_variant	Intron 1 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.92-13959C>T		intron_variant	Intron 1 of 22	1		ENSP00000436652.1
ENSG00000300058	ENST00000768476.1	n.279-953G>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78182 AN: 151802 Hom.: 21734 Cov.: 31

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.815

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.515 AC: 78220 AN: 151922 Hom.: 21739 Cov.: 31 AF XY: 0.526 AC XY: 39084 AN XY: 74244

African (AFR) AF: 0.316 AC: 13075 AN: 41398

American (AMR) AF: 0.476 AC: 7272 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2078 AN: 3468

East Asian (EAS) AF: 0.815 AC: 4223 AN: 5180

South Asian (SAS) AF: 0.802 AC: 3867 AN: 4822

European-Finnish (FIN) AF: 0.714 AC: 7531 AN: 10552

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.568 AC: 38600 AN: 67926

Other (OTH) AF: 0.530 AC: 1111 AN: 2098

Alfa AF: 0.535 Hom.: 11156

Bravo AF: 0.480

Asia WGS AF: 0.739 AC: 2565 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.38
DANN	Benign	0.56
PhyloP100		-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: rs7944040; hg19: chr11-68101356;