rs312788

Positions:

• chr11-68354827-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002335.4(LRP5):​c.489-2823T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 152,014 control chromosomes in the GnomAD database, including 18,686 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 0.47 (18686 hom., cov: 32)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.397

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.489-2823T>G		intron_variant		ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.489-2823T>G		intron_variant		1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5	c.489-2823T>G		intron_variant, NMD_transcript_variant		1		ENSP00000436652

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71044 AN: 151896 Hom.: 18650 Cov.: 32

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.468 AC: 71125 AN: 152014 Hom.: 18686 Cov.: 32 AF XY: 0.457 AC XY: 33936 AN XY: 74332

Gnomad4 AFR AF: 0.693

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.443

Alfa AF: 0.457 Hom.: 3797

Bravo AF: 0.503

Asia WGS AF: 0.197 AC: 692 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	4.2
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs312788; hg19: chr11-68122295;