rs556442

Positions:

• chr11-68425222-G-A
• chr11-68425222-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002335.4(LRP5):​c.3357G>A​(p.Val1119Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,612,708 control chromosomes in the GnomAD database, including 366,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (28392 hom., cov: 32)
  • Exomes 𝑓: 0.67 (337608 hom.)
• Consequence: LRP5 NM_002335.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.318

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 11-68425222-G-A is Benign according to our data. Variant chr11-68425222-G-A is described in ClinVar as [Benign]. Clinvar id is 258638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68425222-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.318 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.3357G>A	p.Val1119Val	synonymous_variant	15/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.3357G>A	p.Val1119Val	synonymous_variant	15/23	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*1963G>A		non_coding_transcript_exon_variant	15/23	1		ENSP00000436652.1
LRP5	ENST00000529993.5	n.*1963G>A		3_prime_UTR_variant	15/23	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86698 AN: 152010 Hom.: 28386 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.876

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.567

GnomAD3 exomes AF: 0.682 AC: 170521 AN: 250022 Hom.: 60581 AF XY: 0.695 AC XY: 94036 AN XY: 135358

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.738

Gnomad SAS exome AF: 0.784

Gnomad FIN exome AF: 0.862

Gnomad NFE exome AF: 0.678

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.674 AC: 984899 AN: 1460580 Hom.: 337608 Cov.: 62 AF XY: 0.679 AC XY: 493444 AN XY: 726700

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.686

Gnomad4 ASJ exome AF: 0.670

Gnomad4 EAS exome AF: 0.677

Gnomad4 SAS exome AF: 0.780

Gnomad4 FIN exome AF: 0.859

Gnomad4 NFE exome AF: 0.672

Gnomad4 OTH exome AF: 0.654

GnomAD4 genome AF: 0.570 AC: 86715 AN: 152128 Hom.: 28392 Cov.: 32 AF XY: 0.584 AC XY: 43445 AN XY: 74380

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.636

Gnomad4 ASJ AF: 0.683

Gnomad4 EAS AF: 0.729

Gnomad4 SAS AF: 0.778

Gnomad4 FIN AF: 0.876

Gnomad4 NFE AF: 0.681

Gnomad4 OTH AF: 0.568

Alfa AF: 0.641 Hom.: 41046

Bravo AF: 0.531

Asia WGS AF: 0.693 AC: 2407 AN: 3478

EpiCase AF: 0.664

EpiControl AF: 0.661

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

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.9
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs556442; hg19: chr11-68192690; COSMIC: COSV53711872;