Genetic Variant LRP5:p.Asp1363Asp (chr11-68436977-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002335.4(LRP5):c.4089C>T(p.Asp1363Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,612 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 17 hom. )

Consequence

LRP5
NM_002335.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.731

Publications

9 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=-0.41).

BP6

Variant 11-68436977-C-T is Benign according to our data. Variant chr11-68436977-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.731 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00213 (325/152362) while in subpopulation EAS AF = 0.0162 (84/5182). AF 95% confidence interval is 0.0134. There are 1 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 AD,AR,SD,Unknown gene

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.4089C>T	p.Asp1363Asp	synonymous	Exon 19 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.2346C>T	p.Asp782Asp	synonymous	Exon 19 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.4089C>T	p.Asp1363Asp	synonymous	Exon 19 of 23	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.*2695C>T		non_coding_transcript_exon	Exon 19 of 23	ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5	TSL:1	n.*2695C>T		3_prime_UTR	Exon 19 of 23	ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0164

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00319

AC:

801

AN:

251114

AF XY:

0.00303

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.0179

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00127

AC:

1854

AN:

1461250

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

925

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000895

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

26130

East Asian (EAS)

AF:

0.0160

AC:

637

AN:

39700

South Asian (SAS)

AF:

0.00173

AC:

149

AN:

86254

European-Finnish (FIN)

AF:

0.0140

AC:

740

AN:

52980

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000145

AC:

161

AN:

1111854

Other (OTH)

AF:

0.00176

AC:

106

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

180

270

360

450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00213

AC:

325

AN:

152362

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

231

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0162

AC:

AN:

5182

South Asian (SAS)

AF:

0.00331

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0185

AC:

197

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000504

Hom.:

Bravo

AF:

0.000990

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Disorder of bone (1)

Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.31

(source)

DANN

Benign

0.96

PhyloP100

-0.73

Mutation Taster

=99/1

polymorphism

(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