rs312778

Positions:

• chr11-68340864-T-C

Variant summary

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

The NM_002335.4(LRP5):​c.92-6983T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 151,974 control chromosomes in the GnomAD database, including 16,676 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 0.44 (16676 hom., cov: 31)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.917

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.92-6983T>C		intron_variant		ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.92-6983T>C		intron_variant		1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5	c.92-6983T>C		intron_variant, NMD_transcript_variant		1		ENSP00000436652

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67439 AN: 151854 Hom.: 16642 Cov.: 31

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.423

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.426

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

GnomAD4 genome AF: 0.444 AC: 67520 AN: 151974 Hom.: 16676 Cov.: 31 AF XY: 0.432 AC XY: 32106 AN XY: 74298

Gnomad4 AFR AF: 0.637

Gnomad4 AMR AF: 0.486

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.422

Alfa AF: 0.421 Hom.: 13725

Bravo AF: 0.481

Asia WGS AF: 0.188 AC: 659 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.027
DANN	Benign	0.35

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: rs312778; hg19: chr11-68108332; COSMIC: COSV53724321;