rs4988322

Positions:

• chr11-68410146-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.2318+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 1,611,592 control chromosomes in the GnomAD database, including 3,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (371 hom., cov: 31)
  • Exomes 𝑓: 0.068 (3555 hom.)
• Consequence: LRP5 NM_002335.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.001634
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.41

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=-0.84).
• BP6: Variant 11-68410146-T-C is Benign according to our data. Variant chr11-68410146-T-C is described in ClinVar as [Benign]. Clinvar id is 258636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68410146-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.2318+6T>C		splice_donor_region_variant, intron_variant		ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.2318+6T>C		splice_donor_region_variant, intron_variant		1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.*924+6T>C		splice_donor_region_variant, intron_variant, NMD_transcript_variant		1
LRP5	ENST00000528714.1	n.112+6T>C		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0635 AC: 9659 AN: 152112 Hom.: 370 Cov.: 31

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0707

Gnomad OTH AF: 0.0703

GnomAD3 exomes AF: 0.0585 AC: 14432 AN: 246616 Hom.: 448 AF XY: 0.0588 AC XY: 7864 AN XY: 133840

Gnomad AFR exome AF: 0.0671

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.0409

Gnomad SAS exome AF: 0.0379

Gnomad FIN exome AF: 0.0452

Gnomad NFE exome AF: 0.0731

Gnomad OTH exome AF: 0.0677

GnomAD4 exome AF: 0.0681 AC: 99338 AN: 1459362 Hom.: 3555 Cov.: 34 AF XY: 0.0672 AC XY: 48768 AN XY: 726062

Gnomad4 AFR exome AF: 0.0666

Gnomad4 AMR exome AF: 0.0466

Gnomad4 ASJ exome AF: 0.0475

Gnomad4 EAS exome AF: 0.0411

Gnomad4 SAS exome AF: 0.0376

Gnomad4 FIN exome AF: 0.0446

Gnomad4 NFE exome AF: 0.0735

Gnomad4 OTH exome AF: 0.0706

GnomAD4 genome AF: 0.0635 AC: 9669 AN: 152230 Hom.: 371 Cov.: 31 AF XY: 0.0618 AC XY: 4602 AN XY: 74422

Gnomad4 AFR AF: 0.0643

Gnomad4 AMR AF: 0.0583

Gnomad4 ASJ AF: 0.0496

Gnomad4 EAS AF: 0.0436

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.0452

Gnomad4 NFE AF: 0.0707

Gnomad4 OTH AF: 0.0705

Alfa AF: 0.0642 Hom.: 166

Bravo AF: 0.0665

Asia WGS AF: 0.0720 AC: 251 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

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	-0.84
CADD	Benign	5.6
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.038
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: rs4988322; hg19: chr11-68177614;