11-68309770-T-C

Variant names:

• chr11-68309770-T-C
• rs312009
• ENST00000816739.1:n.374-1541T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000816739.1(ENSG00000306280):​n.374-1541T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 151,990 control chromosomes in the GnomAD database, including 49,685 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 0.81 (49685 hom., cov: 30)
• Consequence: ENSG00000306280 ENST00000816739.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• Publications: 15 publications found

Genes affected

ENSG00000306280 (HGNC:):

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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	XM_011545029.2	c.118+10772T>C		intron_variant	Intron 1 of 23		XP_011543331.1
LRP5	XM_011545030.2	c.118+10772T>C		intron_variant	Intron 1 of 22		XP_011543332.1
LRP5	XM_011545031.2	c.118+10772T>C		intron_variant	Intron 1 of 23		XP_011543333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000306280	ENST00000816739.1	n.374-1541T>C		intron_variant	Intron 3 of 3
ENSG00000306280	ENST00000816740.1	n.593-1541T>C		intron_variant	Intron 1 of 1
ENSG00000306280	ENST00000816741.1	n.716-1541T>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122556 AN: 151872 Hom.: 49643 Cov.: 30

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.684

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.826

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

GnomAD4 genome AF: 0.807 AC: 122648 AN: 151990 Hom.: 49685 Cov.: 30 AF XY: 0.804 AC XY: 59689 AN XY: 74284

African (AFR) AF: 0.856 AC: 35492 AN: 41484

American (AMR) AF: 0.850 AC: 12964 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2689 AN: 3472

East Asian (EAS) AF: 0.722 AC: 3718 AN: 5150

South Asian (SAS) AF: 0.789 AC: 3793 AN: 4806

European-Finnish (FIN) AF: 0.684 AC: 7227 AN: 10562

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 53976 AN: 67946

Other (OTH) AF: 0.825 AC: 1741 AN: 2110

Alfa AF: 0.802 Hom.: 116085

Bravo AF: 0.824

Asia WGS AF: 0.773 AC: 2686 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.2
DANN	Benign	0.54
PhyloP100		0.0010

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs312009; hg19: chr11-68077238;