rs4988319

chr11-68386720-G-A

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.1412+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,610,102 control chromosomes in the GnomAD database, including 21,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1720 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19662 hom.)
• Consequence: LRP5 NM_002335.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001451
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.538

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=-0.72).
• BP6: Variant 11-68386720-G-A is Benign according to our data. Variant chr11-68386720-G-A is described in ClinVar as [Benign]. Clinvar id is 258633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68386720-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.1412+8G>A		splice_region_variant, intron_variant		ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.1412+8G>A		splice_region_variant, intron_variant		1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.1412+8G>A		splice_region_variant, intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22391 AN: 152170 Hom.: 1719 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.0606

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.153

GnomAD3 exomes AF: 0.136 AC: 33041 AN: 242994 Hom.: 2391 AF XY: 0.133 AC XY: 17599 AN XY: 132474

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.0584

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.160 AC: 232867 AN: 1457814 Hom.: 19662 Cov.: 35 AF XY: 0.157 AC XY: 113760 AN XY: 724958

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.0817

Gnomad4 SAS exome AF: 0.0597

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.147 AC: 22411 AN: 152288 Hom.: 1720 Cov.: 33 AF XY: 0.141 AC XY: 10533 AN XY: 74470

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.0611

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.152

Alfa AF: 0.163 Hom.: 668

Bravo AF: 0.153

Asia WGS AF: 0.0830 AC: 291 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.40
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
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: rs4988319; hg19: chr11-68154188; COSMIC: COSV53722367;