11-68449010-C-T

Position:

chr11-68449010-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002335.4(LRP5):c.4788C>T(p.Thr1596Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,599,766 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 32)

Exomes 𝑓: 0.018 ( 304 hom. )

Consequence

LRP5
NM_002335.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -4.21

Variant links:

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 links:

LRP5 (HGNC:):

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-68449010-C-T is Benign according to our data. Variant chr11-68449010-C-T is described in ClinVar as [Benign]. Clinvar id is 258641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68449010-C-T is described in Lovd as [Benign]. Variant chr11-68449010-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-4.21 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1997/152102) while in subpopulation NFE AF= 0.0196 (1331/67970). AF 95% confidence interval is 0.0187. There are 23 homozygotes in gnomad4. There are 906 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.4788C>T	p.Thr1596Thr	synonymous_variant	23/23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 linkuse as main transcript	c.4788C>T	p.Thr1596Thr	synonymous_variant	23/23	1	NM_002335.4	ENSP00000294304.6		O75197

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1996

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00338

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00859

Gnomad ASJ

AF:

0.0717

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.00292

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.0183

GnomAD3 exomes

AF:

0.0153

AC:

3632

AN:

236966

Hom.:

AF XY:

0.0155

AC XY:

1994

AN XY:

128810

show subpopulations

Gnomad AFR exome

AF:

0.00262

Gnomad AMR exome

AF:

0.00983

Gnomad ASJ exome

AF:

0.0679

Gnomad EAS exome

AF:

0.00225

Gnomad SAS exome

AF:

0.00324

Gnomad FIN exome

AF:

0.00754

Gnomad NFE exome

AF:

0.0205

Gnomad OTH exome

AF:

0.0216

GnomAD4 exome

AF:

0.0180

AC:

26031

AN:

1447664

Hom.:

304

Cov.:

AF XY:

0.0178

AC XY:

12836

AN XY:

720100

show subpopulations

Gnomad4 AFR exome

AF:

0.00239

Gnomad4 AMR exome

AF:

0.00993

Gnomad4 ASJ exome

AF:

0.0718

Gnomad4 EAS exome

AF:

0.00260

Gnomad4 SAS exome

AF:

0.00350

Gnomad4 FIN exome

AF:

0.00759

Gnomad4 NFE exome

AF:

0.0195

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0131

AC:

1997

AN:

152102

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

906

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00337

Gnomad4 AMR

AF:

0.00864

Gnomad4 ASJ

AF:

0.0717

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.00313

Gnomad4 FIN

AF:

0.00603

Gnomad4 NFE

AF:

0.0196

Gnomad4 OTH

AF:

0.0181

Alfa

AF:

0.0174

Hom.:

Bravo

AF:

0.0138

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2019	This variant is associated with the following publications: (PMID: 15981244, 12579474, 16234968, 18721193) -

not specified

Benign:2

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	-	- -

Osteogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.13

DANN

Benign

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over