rs149435615

Positions:

chr11-46890423-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_002334.4(LRP4):c.1769G>A(p.Arg590His) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, LRP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP4	NM_002334.4 linkuse as main transcript	c.1769G>A	p.Arg590His	missense_variant	14/38	ENST00000378623.6
LRP4	XM_017017734.2 linkuse as main transcript	c.1769G>A	p.Arg590His	missense_variant	14/39
LRP4	XM_011520103.3 linkuse as main transcript	c.965G>A	p.Arg322His	missense_variant	8/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6 linkuse as main transcript	c.1769G>A	p.Arg590His	missense_variant	14/38	1	NM_002334.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251214

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000207

AC:

303

AN:

1461824

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

145

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000247

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000224

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 14, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 590 of the LRP4 protein (p.Arg590His). This variant is present in population databases (rs149435615, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LRP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 304882). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cenani-Lenz syndactyly syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2020

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.48

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.40

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.50

Vest4

0.66

MVP

0.73

MPC

1.1

ClinPred

0.062

GERP RS

4.8

Varity_R

0.20

gMVP

0.52

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over