rs6485702

Variant names:

Variant summary

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

The NM_002334.4(LRP4):c.3256A>G(p.Ile1086Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,613,140 control chromosomes in the GnomAD database, including 326,662 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1086L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.51 ( 23301 hom., cov: 30)

Exomes 𝑓: 0.64 ( 303361 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.13

Publications

58 publications found

Variant links:

Genes affected

LRP4 (HGNC:6696): (LDL receptor related protein 4) This gene encodes a member of the low-density lipoprotein receptor-related protein family. The encoded protein may be a regulator of Wnt signaling. Mutations in this gene are associated with Cenani-Lenz syndrome. [provided by RefSeq, May 2010]

LRP4 Gene-Disease associations (from GenCC):

Cenani-Lenz syndactyly syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
congenital myasthenic syndrome 17
Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sclerosteosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sclerosteosis 2
Inheritance: SD Classification: LIMITED Submitted by: Ambry Genetics

LRP4 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 (MetaRNN=1.3157668E-6).

BP6

Variant 11-46877220-T-C is Benign according to our data. Variant chr11-46877220-T-C is described in ClinVar as Benign. ClinVar VariationId is 304872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LRP4	NM_002334.4 link	c.3256A>G	p.Ile1086Val	missense_variant	Exon 23 of 38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2 link	c.3256A>G	p.Ile1086Val	missense_variant	Exon 23 of 39		XP_016873223.1
LRP4	XM_011520103.3 link	c.2452A>G	p.Ile818Val	missense_variant	Exon 17 of 32		XP_011518405.1
LRP4	XM_011520104.3 link	c.1021A>G	p.Ile341Val	missense_variant	Exon 8 of 23		XP_011518406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6 link	c.3256A>G	p.Ile1086Val	missense_variant	Exon 23 of 38	1	NM_002334.4	ENSP00000367888.1

Frequencies

GnomAD3 genomes

AF:

0.515

AC:

78201

AN:

151806

Hom.:

23290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.208

Gnomad AMI

AF:

0.634

Gnomad AMR

AF:

0.569

Gnomad ASJ

AF:

0.734

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.668

Gnomad FIN

AF:

0.623

Gnomad MID

AF:

0.647

Gnomad NFE

AF:

0.663

Gnomad OTH

AF:

0.571

GnomAD2 exomes

AF:

0.586

AC:

147226

AN:

251342

AF XY:

0.605

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.731

Gnomad EAS exome

AF:

0.284

Gnomad FIN exome

AF:

0.631

Gnomad NFE exome

AF:

0.672

Gnomad OTH exome

AF:

0.654

GnomAD4 exome

AF:

0.636

AC:

929801

AN:

1461214

Hom.:

303361

Cov.:

AF XY:

0.640

AC XY:

465231

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.194

AC:

6491

AN:

33462

American (AMR)

AF:

0.501

AC:

22412

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.732

AC:

19123

AN:

26130

East Asian (EAS)

AF:

0.296

AC:

11765

AN:

39692

South Asian (SAS)

AF:

0.662

AC:

57095

AN:

86240

European-Finnish (FIN)

AF:

0.636

AC:

33996

AN:

53416

Middle Eastern (MID)

AF:

0.661

AC:

3811

AN:

5762

European-Non Finnish (NFE)

AF:

0.663

AC:

737256

AN:

1111432

Other (OTH)

AF:

0.627

AC:

37852

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

18761

37522

56284

75045

93806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18818

37636

56454

75272

94090

<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:

0.515

AC:

78217

AN:

151926

Hom.:

23301

Cov.:

AF XY:

0.515

AC XY:

38233

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.208

AC:

8609

AN:

41422

American (AMR)

AF:

0.569

AC:

8680

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.734

AC:

2545

AN:

3466

East Asian (EAS)

AF:

0.296

AC:

1522

AN:

5142

South Asian (SAS)

AF:

0.669

AC:

3220

AN:

4816

European-Finnish (FIN)

AF:

0.623

AC:

6575

AN:

10562

Middle Eastern (MID)

AF:

0.647

AC:

189

AN:

292

European-Non Finnish (NFE)

AF:

0.663

AC:

45079

AN:

67946

Other (OTH)

AF:

0.578

AC:

1221

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1628

3255

4883

6510

8138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.638

Hom.:

100290

Bravo

AF:

0.494

TwinsUK

AF:

0.669

AC:

2479

ALSPAC

AF:

0.656

AC:

2528

ESP6500AA

AF:

0.222

AC:

977

ESP6500EA

AF:

0.667

AC:

5733

ExAC

AF:

0.585

AC:

70996

Asia WGS

AF:

0.530

AC:

1847

AN:

3478

EpiCase

AF:

0.678

EpiControl

AF:

0.683

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 28, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cenani-Lenz syndactyly syndrome

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19079262, 23321396) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital myasthenic syndrome 17

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sclerosteosis 2

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.10

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0000013

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.20

PhyloP100

2.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.12

REVEL

Benign

0.22

Sift

Benign

0.81

Sift4G

Benign

0.55

Polyphen

0.0

Vest4

0.058

MPC

0.45

ClinPred

0.0017

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.42

Mutation Taster

=98/2

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