rs4988327

Variant names:

• chr11-68310198-A-G
• rs4988327
• ENST00000816739.1:n.374-1113A>G

Variant summary

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

The ENST00000816739.1(ENSG00000306280):​n.374-1113A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0562 in 152,226 control chromosomes in the GnomAD database, including 287 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 0.056 (287 hom., cov: 31)
• Consequence: ENSG00000306280 ENST00000816739.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	XM_011545029.2	c.118+11200A>G		intron_variant	Intron 1 of 23		XP_011543331.1
LRP5	XM_011545030.2	c.118+11200A>G		intron_variant	Intron 1 of 22		XP_011543332.1
LRP5	XM_011545031.2	c.118+11200A>G		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.374-1113A>G		intron_variant	Intron 3 of 3
ENSG00000306280	ENST00000816740.1	n.593-1113A>G		intron_variant	Intron 1 of 1
ENSG00000306280	ENST00000816741.1	n.716-1113A>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8550 AN: 152108 Hom.: 287 Cov.: 31

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0806

Gnomad OTH AF: 0.0771

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

GnomAD4 genome AF: 0.0562 AC: 8558 AN: 152226 Hom.: 287 Cov.: 31 AF XY: 0.0546 AC XY: 4060 AN XY: 74418

African (AFR) AF: 0.0245 AC: 1018 AN: 41526

American (AMR) AF: 0.0632 AC: 966 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 175 AN: 3470

East Asian (EAS) AF: 0.0139 AC: 72 AN: 5180

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4828

European-Finnish (FIN) AF: 0.0369 AC: 391 AN: 10610

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0806 AC: 5484 AN: 68002

Other (OTH) AF: 0.0758 AC: 160 AN: 2110

Alfa AF: 0.0670 Hom.: 69

Bravo AF: 0.0583

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.88
PhyloP100		-0.027

Splicing

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

Other links and lift over

dbSNP: rs4988327; hg19: chr11-68077666;