11-68449010-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. T1596T) has been classified as Likely 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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

bone mineral density quantitative trait locus 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
exudative vitreoretinopathy 4
Inheritance: AD, SD, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
inherited retinal dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
osteoporosis-pseudoglioma syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant osteosclerosis, Worth type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
polycystic liver disease 4 with or without kidney cysts
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal dominant osteopetrosis 1
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
exudative vitreoretinopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hyperostosis corticalis generalisata
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteosclerosis-developmental delay-craniosynostosis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
polycystic liver disease 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.008).

BP6

Variant 11-68449010-C-T is Benign according to our data. Variant chr11-68449010-C-T is described in ClinVar as Benign. ClinVar VariationId is 258641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR,SD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.4788C>T	p.Thr1596Thr	synonymous_variant	Exon 23 of 23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 link	c.4788C>T	p.Thr1596Thr	synonymous_variant	Exon 23 of 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

GnomAD2 exomes

AF:

0.0153

AC:

3632

AN:

236966

AF XY:

0.0155

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 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

African (AFR)

AF:

0.00239

AC:

AN:

33460

American (AMR)

AF:

0.00993

AC:

443

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.0718

AC:

1845

AN:

25694

East Asian (EAS)

AF:

0.00260

AC:

103

AN:

39672

South Asian (SAS)

AF:

0.00350

AC:

300

AN:

85820

European-Finnish (FIN)

AF:

0.00759

AC:

332

AN:

43766

Middle Eastern (MID)

AF:

0.0202

AC:

116

AN:

5738

European-Non Finnish (NFE)

AF:

0.0195

AC:

21597

AN:

1108760

Other (OTH)

AF:

0.0202

AC:

1215

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1412

2823

4235

5646

7058

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

794

1588

2382

3176

3970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0131

AC:

1997

AN:

152102

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

906

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00337

AC:

140

AN:

41494

American (AMR)

AF:

0.00864

AC:

132

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0717

AC:

249

AN:

3472

East Asian (EAS)

AF:

0.00347

AC:

AN:

5182

South Asian (SAS)

AF:

0.00313

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00603

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0196

AC:

1331

AN:

67970

Other (OTH)

AF:

0.0181

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

101

201

302

402

503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0180

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15981244, 12579474, 16234968, 18721193) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 27, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Osteogenesis imperfecta

Benign:1

May 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.13

(source)

DANN

Benign

0.62

PhyloP100

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over