11-46894628-T-G

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.1501A>C(p.Asn501His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,212 control chromosomes in the GnomAD database, including 1,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N501N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 129 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1330 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.67

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 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=0.0063460767).

BP6

Variant 11-46894628-T-G is Benign according to our data. Variant chr11-46894628-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	NM_002334.4	MANE Select	c.1501A>C	p.Asn501His	missense	Exon 12 of 38	NP_002325.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.1501A>C	p.Asn501His	missense	Exon 12 of 38	ENSP00000367888.1
	LRP4	ENST00000858258.1		c.1501A>C	p.Asn501His	missense	Exon 12 of 35	ENSP00000528317.1

Frequencies

GnomAD3 genomes

AF:

0.0316

AC:

4808

AN:

152182

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00767

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0311

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0132

Gnomad FIN

AF:

0.0749

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0432

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0345

AC:

8591

AN:

249058

AF XY:

0.0351

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0370

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0714

Gnomad NFE exome

AF:

0.0447

Gnomad OTH exome

AF:

0.0488

GnomAD4 exome

AF:

0.0397

AC:

57935

AN:

1460912

Hom.:

1330

Cov.:

AF XY:

0.0392

AC XY:

28494

AN XY:

726676

show subpopulations

African (AFR)

AF:

0.00621

AC:

208

AN:

33476

American (AMR)

AF:

0.0262

AC:

1167

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

941

AN:

26110

East Asian (EAS)

AF:

0.000101

AC:

AN:

39688

South Asian (SAS)

AF:

0.0137

AC:

1180

AN:

86102

European-Finnish (FIN)

AF:

0.0752

AC:

4011

AN:

53364

Middle Eastern (MID)

AF:

0.0645

AC:

372

AN:

5764

European-Non Finnish (NFE)

AF:

0.0429

AC:

47731

AN:

1111516

Other (OTH)

AF:

0.0384

AC:

2321

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

3149

6298

9446

12595

15744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1706

3412

5118

6824

8530

<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:

0.0315

AC:

4803

AN:

152300

Hom.:

129

Cov.:

AF XY:

0.0317

AC XY:

2364

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00763

AC:

317

AN:

41568

American (AMR)

AF:

0.0311

AC:

475

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

103

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0130

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0749

AC:

795

AN:

10616

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0432

AC:

2936

AN:

68010

Other (OTH)

AF:

0.0345

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

250

500

750

1000

1250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0383

Hom.:

490

Bravo

AF:

0.0281

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0407

AC:

157

ESP6500AA

AF:

0.00818

AC:

ESP6500EA

AF:

0.0435

AC:

374

ExAC

AF:

0.0334

AC:

4051

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cenani-Lenz syndactyly syndrome (1)

Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0063

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.94

PhyloP100

7.7

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.42

Sift

Benign

0.072

Sift4G

Benign

0.13

Polyphen

0.29

Vest4

0.23

MPC

0.84

ClinPred

0.015

GERP RS

5.7

Varity_R

0.29

gMVP

0.67

Mutation Taster

=81/19

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