rs117936904

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002334.4(LRP4):c.5165T>A(p.Leu1722His) variant causes a missense change. The variant allele was found at a frequency of 0.0206 in 1,611,148 control chromosomes in the GnomAD database, including 438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 50 hom., cov: 32)

Exomes 𝑓: 0.021 ( 388 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.74

Publications

12 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 links:

LRP4-AS1 (HGNC:44128): (LRP4 antisense RNA 1)

LRP4-AS1 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=0.007769525).

BP6

Variant 11-46864526-A-T is Benign according to our data. Variant chr11-46864526-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0178 (2711/152350) while in subpopulation NFE AF = 0.0228 (1552/68036). AF 95% confidence interval is 0.0219. There are 50 homozygotes in GnomAd4. There are 1366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 50 AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP4	NM_002334.4 link	c.5165T>A	p.Leu1722His	missense_variant	Exon 36 of 38	ENST00000378623.6	NP_002325.2	O75096

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP4	ENST00000378623.6 link	c.5165T>A	p.Leu1722His	missense_variant	Exon 36 of 38	1	NM_002334.4	ENSP00000367888.1	O75096
LRP4-AS1	ENST00000502049.4 link	n.197-8548A>T		intron_variant	Intron 2 of 2	2
LRP4-AS1	ENST00000531719.5 link	n.292-8548A>T		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2713

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0619

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0228

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0194

AC:

4875

AN:

250854

AF XY:

0.0196

show subpopulations

Gnomad AFR exome

AF:

0.00339

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0576

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0209

AC:

30531

AN:

1458798

Hom.:

388

Cov.:

AF XY:

0.0204

AC XY:

14826

AN XY:

726026

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33430

American (AMR)

AF:

0.0139

AC:

621

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

426

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39670

South Asian (SAS)

AF:

0.00505

AC:

435

AN:

86206

European-Finnish (FIN)

AF:

0.0590

AC:

3143

AN:

53314

Middle Eastern (MID)

AF:

0.0179

AC:

103

AN:

5758

European-Non Finnish (NFE)

AF:

0.0221

AC:

24501

AN:

1109300

Other (OTH)

AF:

0.0198

AC:

1196

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1297

2594

3892

5189

6486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

884

1768

2652

3536

4420

<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:

0.0178

AC:

2711

AN:

152350

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1366

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00365

AC:

152

AN:

41588

American (AMR)

AF:

0.0148

AC:

227

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00580

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0619

AC:

657

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0228

AC:

1552

AN:

68036

Other (OTH)

AF:

0.0166

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

133

266

399

532

665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0209

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0221

AC:

190

ExAC

AF:

0.0186

AC:

2257

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0248

EpiControl

AF:

0.0247

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cenani-Lenz syndactyly syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely 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

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0078

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.7

PhyloP100

6.7

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.69

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

Sift4G

Benign

0.074

Polyphen

0.99

Vest4

0.35

MPC

0.26

ClinPred

0.022

GERP RS

6.0

Varity_R

0.33

gMVP

0.84

Mutation Taster

=54/46

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