rs148685646

Positions:

• chr11-68433847-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002335.4(LRP5):​c.4000+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,610,128 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (31 hom.)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.348

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-68433847-C-T is Benign according to our data. Variant chr11-68433847-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36481.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=5}. Variant chr11-68433847-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00499 (7280/1457792) while in subpopulation MID AF= 0.0196 (111/5658). AF 95% confidence interval is 0.0167. There are 31 homozygotes in gnomad4_exome. There are 3676 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.4000+9C>T		intron_variant		ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.4000+9C>T		intron_variant		1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*2606+9C>T		intron_variant		1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152218 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00548

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00524 AC: 1246 AN: 237960 Hom.: 7 AF XY: 0.00535 AC XY: 699 AN XY: 130606

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00433

Gnomad FIN exome AF: 0.000196

Gnomad NFE exome AF: 0.00550

Gnomad OTH exome AF: 0.00970

GnomAD4 exome AF: 0.00499 AC: 7280 AN: 1457792 Hom.: 31 Cov.: 32 AF XY: 0.00507 AC XY: 3676 AN XY: 725252

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00402

Gnomad4 FIN exome AF: 0.000597

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00625

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152336 Hom.: 3 Cov.: 33 AF XY: 0.00407 AC XY: 303 AN XY: 74490

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00548

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00717 Hom.: 7

Bravo AF: 0.00427

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	LRP5: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 28, 2021	- -

Postmenopausal osteoporosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 13, 2021

- -

Increased bone mineral density Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.4
DANN	Benign	0.90

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: rs148685646; hg19: chr11-68201315;