NM_002335.4:c.3357G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002335.4(LRP5):c.3357G>A(p.Val1119Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,612,708 control chromosomes in the GnomAD database, including 366,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 28392 hom., cov: 32)

Exomes 𝑓: 0.67 ( 337608 hom. )

Consequence

LRP5
NM_002335.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.318

Publications

62 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 11-68425222-G-A is Benign according to our data. Variant chr11-68425222-G-A is described in ClinVar as Benign. ClinVar VariationId is 258638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.318 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 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.3357G>A	p.Val1119Val	synonymous	Exon 15 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.1614G>A	p.Val538Val	synonymous	Exon 15 of 23	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.3357G>A	p.Val1119Val	synonymous	Exon 15 of 23	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.*1963G>A		non_coding_transcript_exon	Exon 15 of 23	ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5	TSL:1	n.*1963G>A		3_prime_UTR	Exon 15 of 23	ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.570

AC:

86698

AN:

152010

Hom.:

28386

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.414

Gnomad AMR

AF:

0.636

Gnomad ASJ

AF:

0.683

Gnomad EAS

AF:

0.729

Gnomad SAS

AF:

0.779

Gnomad FIN

AF:

0.876

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.681

Gnomad OTH

AF:

0.567

GnomAD2 exomes

AF:

0.682

AC:

170521

AN:

250022

AF XY:

0.695

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.688

Gnomad ASJ exome

AF:

0.669

Gnomad EAS exome

AF:

0.738

Gnomad FIN exome

AF:

0.862

Gnomad NFE exome

AF:

0.678

Gnomad OTH exome

AF:

0.671

GnomAD4 exome

AF:

0.674

AC:

984899

AN:

1460580

Hom.:

337608

Cov.:

AF XY:

0.679

AC XY:

493444

AN XY:

726700

show subpopulations

African (AFR)

AF:

0.220

AC:

7370

AN:

33478

American (AMR)

AF:

0.686

AC:

30656

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.670

AC:

17518

AN:

26132

East Asian (EAS)

AF:

0.677

AC:

26879

AN:

39698

South Asian (SAS)

AF:

0.780

AC:

67286

AN:

86252

European-Finnish (FIN)

AF:

0.859

AC:

44930

AN:

52306

Middle Eastern (MID)

AF:

0.548

AC:

3152

AN:

5750

European-Non Finnish (NFE)

AF:

0.672

AC:

747625

AN:

1111894

Other (OTH)

AF:

0.654

AC:

39483

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

18340

36680

55021

73361

91701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19192

38384

57576

76768

95960

<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:

0.570

AC:

86715

AN:

152128

Hom.:

28392

Cov.:

AF XY:

0.584

AC XY:

43445

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.237

AC:

9849

AN:

41524

American (AMR)

AF:

0.636

AC:

9729

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.683

AC:

2372

AN:

3472

East Asian (EAS)

AF:

0.729

AC:

3758

AN:

5156

South Asian (SAS)

AF:

0.778

AC:

3752

AN:

4820

European-Finnish (FIN)

AF:

0.876

AC:

9289

AN:

10602

Middle Eastern (MID)

AF:

0.480

AC:

141

AN:

294

European-Non Finnish (NFE)

AF:

0.681

AC:

46250

AN:

67950

Other (OTH)

AF:

0.568

AC:

1198

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1581

3162

4743

6324

7905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.629

Hom.:

49386

Bravo

AF:

0.531

Asia WGS

AF:

0.693

AC:

2407

AN:

3478

EpiCase

AF:

0.664

EpiControl

AF:

0.661

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.9

(source)

DANN

Benign

0.72

PhyloP100

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=95/5

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