11-68403545-T-C

Position:

• chr11-68403545-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002335.4(LRP5):​c.1647T>C​(p.Phe549Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 1,614,072 control chromosomes in the GnomAD database, including 659,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54985 hom., cov: 32)
  • Exomes 𝑓: 0.91 (604642 hom.)
• Consequence: LRP5 NM_002335.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0750

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]

LRP5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-68403545-T-C is Benign according to our data. Variant chr11-68403545-T-C is described in ClinVar as [Benign]. Clinvar id is 258634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68403545-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-68403545-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.1647T>C	p.Phe549Phe	synonymous_variant	8/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.1647T>C	p.Phe549Phe	synonymous_variant	8/23	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*59T>C		non_coding_transcript_exon_variant	7/23	1		ENSP00000436652.1
LRP5	ENST00000529993.5	n.*59T>C		3_prime_UTR_variant	7/23	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.840 AC: 127718 AN: 152124 Hom.: 54955 Cov.: 32

Gnomad AFR AF: 0.633

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.889

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.927

Gnomad FIN AF: 0.970

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.848

GnomAD3 exomes AF: 0.906 AC: 227863 AN: 251440 Hom.: 104064 AF XY: 0.911 AC XY: 123761 AN XY: 135908

Gnomad AFR exome AF: 0.625

Gnomad AMR exome AF: 0.936

Gnomad ASJ exome AF: 0.890

Gnomad EAS exome AF: 0.989

Gnomad SAS exome AF: 0.923

Gnomad FIN exome AF: 0.964

Gnomad NFE exome AF: 0.910

Gnomad OTH exome AF: 0.903

GnomAD4 exome AF: 0.908 AC: 1327694 AN: 1461830 Hom.: 604642 Cov.: 67 AF XY: 0.910 AC XY: 661464 AN XY: 727230

Gnomad4 AFR exome AF: 0.625

Gnomad4 AMR exome AF: 0.932

Gnomad4 ASJ exome AF: 0.892

Gnomad4 EAS exome AF: 0.976

Gnomad4 SAS exome AF: 0.920

Gnomad4 FIN exome AF: 0.962

Gnomad4 NFE exome AF: 0.911

Gnomad4 OTH exome AF: 0.893

GnomAD4 genome AF: 0.839 AC: 127799 AN: 152242 Hom.: 54985 Cov.: 32 AF XY: 0.845 AC XY: 62913 AN XY: 74436

Gnomad4 AFR AF: 0.633

Gnomad4 AMR AF: 0.889

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.984

Gnomad4 SAS AF: 0.927

Gnomad4 FIN AF: 0.970

Gnomad4 NFE AF: 0.912

Gnomad4 OTH AF: 0.849

Alfa AF: 0.893 Hom.: 102677

Bravo AF: 0.825

Asia WGS AF: 0.926 AC: 3219 AN: 3478

EpiCase AF: 0.908

EpiControl AF: 0.908

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30747064) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.2
DANN	Benign	0.61

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: rs545382; hg19: chr11-68171013; COSMIC: COSV53718067; COSMIC: COSV53718067;