rs314776

chr11-68365567-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002335.4(LRP5):c.884-4T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,613,252 control chromosomes in the GnomAD database, including 139,962 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18654 hom., cov: 29)
  • Exomes 𝑓: 0.39 (121308 hom.)
• Consequence: LRP5 NM_002335.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000005640
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.249

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-68365567-T-C is Benign according to our data. Variant chr11-68365567-T-C is described in ClinVar as [Benign]. Clinvar id is 258642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68365567-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.884-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.884-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.884-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70891 AN: 151690 Hom.: 18618 Cov.: 29

Gnomad AFR AF: 0.694

Gnomad AMI AF: 0.642

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.446

GnomAD3 exomes AF: 0.378 AC: 94789 AN: 250626 Hom.: 20935 AF XY: 0.360 AC XY: 48763 AN XY: 135562

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.535

Gnomad ASJ exome AF: 0.382

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.395 AC: 576786 AN: 1461444 Hom.: 121308 Cov.: 47 AF XY: 0.386 AC XY: 280961 AN XY: 727020

Gnomad4 AFR exome AF: 0.712

Gnomad4 AMR exome AF: 0.531

Gnomad4 ASJ exome AF: 0.388

Gnomad4 EAS exome AF: 0.0935

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.413

Gnomad4 OTH exome AF: 0.401

GnomAD4 genome AF: 0.468 AC: 70973 AN: 151808 Hom.: 18654 Cov.: 29 AF XY: 0.456 AC XY: 33840 AN XY: 74182

Gnomad4 AFR AF: 0.694

Gnomad4 AMR AF: 0.496

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.442

Alfa AF: 0.436 Hom.: 6570

Bravo AF: 0.503

Asia WGS AF: 0.197 AC: 692 AN: 3478

EpiCase AF: 0.420

EpiControl AF: 0.417

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 24, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.5
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000056
dbscSNV1_RF	Benign	0.0
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: rs314776; hg19: chr11-68133035; COSMIC: COSV53714341;