rs576118

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2318+100G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 933,354 control chromosomes in the GnomAD database, including 266,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 38384 hom., cov: 32)

Exomes 𝑓: 0.76 ( 228526 hom. )

Consequence

LRP5
NM_002335.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.44

Publications

15 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=-0.91).

BP6

Variant 11-68410240-G-A is Benign according to our data. Variant chr11-68410240-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.819 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.2318+100G>A		intron	N/A	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.575+100G>A		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.2318+100G>A	intron	N/A	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.*924+100G>A	intron	N/A	ENSP00000436652.1	E9PHY1
LRP5	ENST00000909991.1		c.2381+100G>A	intron	N/A	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

106042

AN:

151968

Hom.:

38379

Cov.:

show subpopulations

Gnomad AFR

AF:

0.507

Gnomad AMI

AF:

0.461

Gnomad AMR

AF:

0.719

Gnomad ASJ

AF:

0.752

Gnomad EAS

AF:

0.782

Gnomad SAS

AF:

0.841

Gnomad FIN

AF:

0.927

Gnomad MID

AF:

0.690

Gnomad NFE

AF:

0.757

Gnomad OTH

AF:

0.692

GnomAD4 exome

AF:

0.762

AC:

595480

AN:

781268

Hom.:

228526

AF XY:

0.767

AC XY:

312908

AN XY:

408172

show subpopulations

African (AFR)

AF:

0.505

AC:

10110

AN:

20026

American (AMR)

AF:

0.738

AC:

25885

AN:

35090

Ashkenazi Jewish (ASJ)

AF:

0.738

AC:

15752

AN:

21342

East Asian (EAS)

AF:

0.736

AC:

24324

AN:

33048

South Asian (SAS)

AF:

0.836

AC:

55742

AN:

66700

European-Finnish (FIN)

AF:

0.913

AC:

41241

AN:

45152

Middle Eastern (MID)

AF:

0.740

AC:

2304

AN:

3114

European-Non Finnish (NFE)

AF:

0.755

AC:

392064

AN:

519124

Other (OTH)

AF:

0.745

AC:

28058

AN:

37672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

8234

16467

24701

32934

41168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5974

11948

17922

23896

29870

<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:

0.697

AC:

106078

AN:

152086

Hom.:

38384

Cov.:

AF XY:

0.709

AC XY:

52727

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.507

AC:

20999

AN:

41438

American (AMR)

AF:

0.719

AC:

10991

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.752

AC:

2607

AN:

3468

East Asian (EAS)

AF:

0.782

AC:

4040

AN:

5164

South Asian (SAS)

AF:

0.840

AC:

4056

AN:

4826

European-Finnish (FIN)

AF:

0.927

AC:

9823

AN:

10600

Middle Eastern (MID)

AF:

0.680

AC:

200

AN:

294

European-Non Finnish (NFE)

AF:

0.757

AC:

51479

AN:

67992

Other (OTH)

AF:

0.693

AC:

1463

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1549

3099

4648

6198

7747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.731

Hom.:

47829

Bravo

AF:

0.667

Asia WGS

AF:

0.789

AC:

2742

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

-0.91

CADD

Benign

0.10

(source)

DANN

Benign

0.53

PhyloP100

-3.4

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