chr11-46878979-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_002334.4(LRP4):c.3064A>G(p.Asn1022Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,078 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.74

Publications

5 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 -9 ACMG points.

BP6

Variant 11-46878979-T-C is Benign according to our data. Variant chr11-46878979-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 304873.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00094 (143/152190) while in subpopulation NFE AF = 0.00166 (113/68042). AF 95% confidence interval is 0.00141. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP4	NM_002334.4 link	c.3064A>G	p.Asn1022Asp	missense_variant	Exon 22 of 38	ENST00000378623.6	NP_002325.2	O75096
LRP4	XM_017017734.2 link	c.3064A>G	p.Asn1022Asp	missense_variant	Exon 22 of 39		XP_016873223.1
LRP4	XM_011520103.3 link	c.2260A>G	p.Asn754Asp	missense_variant	Exon 16 of 32		XP_011518405.1
LRP4	XM_011520104.3 link	c.829A>G	p.Asn277Asp	missense_variant	Exon 7 of 23		XP_011518406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6 link	c.3064A>G	p.Asn1022Asp	missense_variant	Exon 22 of 38	1	NM_002334.4	ENSP00000367888.1		O75096

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00102

AC:

257

AN:

251466

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00185

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00110

AC:

1610

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

754

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00131

AC:

1454

AN:

1112008

Other (OTH)

AF:

0.000960

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

196

295

393

491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000940

AC:

143

AN:

152190

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41444

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00166

AC:

113

AN:

68042

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.000638

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00132

AC:

160

EpiCase

AF:

0.000872

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 13, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 11, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Cenani-Lenz syndactyly syndrome

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

LRP4-related disorder

Benign:1

Feb 11, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

M_CAP

Benign

0.022

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.96

PhyloP100

1.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

REVEL

Benign

0.11

Sift

Benign

0.51

Sift4G

Benign

0.62

Polyphen

0.0010

Vest4

0.18

MVP

0.45

MPC

0.63

ClinPred

0.012

GERP RS

4.3

Varity_R

0.13

gMVP

0.55

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr11-46878979-T-C

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