rs2306033

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.3608C>T(p.Ala1203Val) variant causes a missense change. The variant allele was found at a frequency of 0.155 in 1,613,704 control chromosomes in the GnomAD database, including 27,679 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. A1203T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 2454 hom., cov: 31)

Exomes 𝑓: 0.16 ( 25225 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.72

Publications

46 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=3.744471E-5).

BP6

Variant 11-46875895-G-A is Benign according to our data. Variant chr11-46875895-G-A is described in ClinVar as Benign. ClinVar VariationId is 304869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP4	NM_002334.4 link	c.3608C>T	p.Ala1203Val	missense_variant	Exon 26 of 38	ENST00000378623.6	NP_002325.2	O75096
LRP4	XM_017017734.2 link	c.3608C>T	p.Ala1203Val	missense_variant	Exon 26 of 39		XP_016873223.1
LRP4	XM_011520103.3 link	c.2804C>T	p.Ala935Val	missense_variant	Exon 20 of 32		XP_011518405.1
LRP4	XM_011520104.3 link	c.1373C>T	p.Ala458Val	missense_variant	Exon 11 of 23		XP_011518406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6 link	c.3608C>T	p.Ala1203Val	missense_variant	Exon 26 of 38	1	NM_002334.4	ENSP00000367888.1		O75096

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21059

AN:

151922

Hom.:

2443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0302

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.0599

Gnomad EAS

AF:

0.603

Gnomad SAS

AF:

0.204

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.132

Gnomad OTH

AF:

0.122

GnomAD2 exomes

AF:

0.209

AC:

52497

AN:

251278

AF XY:

0.200

show subpopulations

Gnomad AFR exome

AF:

0.0285

Gnomad AMR exome

AF:

0.398

Gnomad ASJ exome

AF:

0.0563

Gnomad EAS exome

AF:

0.622

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.152

GnomAD4 exome

AF:

0.157

AC:

229334

AN:

1461664

Hom.:

25225

Cov.:

AF XY:

0.157

AC XY:

113960

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0219

AC:

733

AN:

33476

American (AMR)

AF:

0.377

AC:

16851

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0586

AC:

1532

AN:

26134

East Asian (EAS)

AF:

0.618

AC:

24531

AN:

39700

South Asian (SAS)

AF:

0.201

AC:

17339

AN:

86246

European-Finnish (FIN)

AF:

0.230

AC:

12267

AN:

53410

Middle Eastern (MID)

AF:

0.106

AC:

614

AN:

5768

European-Non Finnish (NFE)

AF:

0.132

AC:

146443

AN:

1111834

Other (OTH)

AF:

0.149

AC:

9024

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

11413

22825

34238

45650

57063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5652

11304

16956

22608

28260

<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:

0.139

AC:

21072

AN:

152040

Hom.:

2454

Cov.:

AF XY:

0.149

AC XY:

11068

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0302

AC:

1252

AN:

41514

American (AMR)

AF:

0.233

AC:

3556

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0599

AC:

208

AN:

3472

East Asian (EAS)

AF:

0.604

AC:

3093

AN:

5124

South Asian (SAS)

AF:

0.204

AC:

982

AN:

4812

European-Finnish (FIN)

AF:

0.249

AC:

2636

AN:

10566

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.132

AC:

8986

AN:

67956

Other (OTH)

AF:

0.119

AC:

252

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

847

1694

2540

3387

4234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.136

Hom.:

6851

Bravo

AF:

0.137

TwinsUK

AF:

0.127

AC:

470

ALSPAC

AF:

0.136

AC:

525

ESP6500AA

AF:

0.0336

AC:

148

ESP6500EA

AF:

0.122

AC:

1051

ExAC

AF:

0.194

AC:

23606

Asia WGS

AF:

0.313

AC:

1085

AN:

3478

EpiCase

AF:

0.120

EpiControl

AF:

0.112

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cenani-Lenz syndactyly syndrome

Benign:1

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. -

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

0.056

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.23

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.70

MetaRNN

Benign

0.000037

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.1

PhyloP100

3.7

PrimateAI

Benign

0.34

PROVEAN

Benign

0.18

REVEL

Benign

0.23

Sift

Benign

0.91

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.025

MPC

0.54

ClinPred

0.011

GERP RS

5.7

Varity_R

0.027

gMVP

0.26

Mutation Taster

=90/10

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