NM_002335.4:c.4348+23T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002335.4(LRP5):c.4348+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,602,452 control chromosomes in the GnomAD database, including 6,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.098 ( 881 hom., cov: 33)

Exomes 𝑓: 0.085 ( 5557 hom. )

Consequence

LRP5
NM_002335.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.60

Publications

17 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
LRP5-related exudative vitreoretinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
osteoporosis-pseudoglioma syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
exudative vitreoretinopathy 4
Inheritance: Unknown, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal dominant osteosclerosis, Worth type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
polycystic liver disease 4 with or without kidney cysts
Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
autosomal dominant osteopetrosis 1
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 11-68438705-T-C is Benign according to our data. Variant chr11-68438705-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002335.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.4348+23T>C		intron	N/A	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.2605+23T>C		intron	N/A	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.4348+23T>C	intron	N/A	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.*2954+23T>C	intron	N/A	ENSP00000436652.1	E9PHY1
LRP5	ENST00000909991.1		c.4411+23T>C	intron	N/A	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.0982

AC:

14944

AN:

152176

Hom.:

880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.215

Gnomad AMR

AF:

0.0744

Gnomad ASJ

AF:

0.0919

Gnomad EAS

AF:

0.0434

Gnomad SAS

AF:

0.0447

Gnomad FIN

AF:

0.0502

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.0868

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.0749

AC:

18122

AN:

242098

AF XY:

0.0740

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.0547

Gnomad ASJ exome

AF:

0.0890

Gnomad EAS exome

AF:

0.0382

Gnomad FIN exome

AF:

0.0501

Gnomad NFE exome

AF:

0.0894

Gnomad OTH exome

AF:

0.0813

GnomAD4 exome

AF:

0.0849

AC:

123106

AN:

1450158

Hom.:

5557

Cov.:

AF XY:

0.0835

AC XY:

60256

AN XY:

721952

show subpopulations

African (AFR)

AF:

0.153

AC:

5114

AN:

33340

American (AMR)

AF:

0.0581

AC:

2593

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.0894

AC:

2329

AN:

26062

East Asian (EAS)

AF:

0.0455

AC:

1806

AN:

39650

South Asian (SAS)

AF:

0.0395

AC:

3398

AN:

86084

European-Finnish (FIN)

AF:

0.0490

AC:

2366

AN:

48272

Middle Eastern (MID)

AF:

0.135

AC:

754

AN:

5598

European-Non Finnish (NFE)

AF:

0.0897

AC:

99259

AN:

1106414

Other (OTH)

AF:

0.0913

AC:

5487

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

6161

12323

18484

24646

30807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3640

7280

10920

14560

18200

<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:

0.0982

AC:

14956

AN:

152294

Hom.:

881

Cov.:

AF XY:

0.0949

AC XY:

7068

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.148

AC:

6159

AN:

41550

American (AMR)

AF:

0.0742

AC:

1135

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0919

AC:

319

AN:

3472

East Asian (EAS)

AF:

0.0433

AC:

224

AN:

5178

South Asian (SAS)

AF:

0.0449

AC:

217

AN:

4828

European-Finnish (FIN)

AF:

0.0502

AC:

533

AN:

10622

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0868

AC:

5908

AN:

68026

Other (OTH)

AF:

0.103

AC:

218

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

723

1446

2170

2893

3616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0918

Hom.:

471

Bravo

AF:

0.105

Asia WGS

AF:

0.0750

AC:

263

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.2

(source)

DANN

Benign

0.37

PhyloP100

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over