rs6485702

Positions:

chr11-46877220-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002334.4(LRP4):c.3256A>G(p.Ile1086Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,613,140 control chromosomes in the GnomAD database, including 326,662 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 23301 hom., cov: 30)

Exomes 𝑓: 0.64 ( 303361 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.13

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 Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP4. . Gene score misZ 3.0632 (greater than the threshold 3.09). Trascript score misZ 5.2056 (greater than threshold 3.09). GenCC has associacion of gene with postsynaptic congenital myasthenic syndrome, sclerosteosis, Cenani-Lenz syndactyly syndrome, sclerosteosis 2, congenital myasthenic syndrome 17.

BP4

Computational evidence support a benign effect (MetaRNN=1.3157668E-6).

BP6

Variant 11-46877220-T-C is Benign according to our data. Variant chr11-46877220-T-C is described in ClinVar as [Benign]. Clinvar id is 304872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46877220-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LRP4	NM_002334.4 linkuse as main transcript	c.3256A>G	p.Ile1086Val	missense_variant	23/38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2 linkuse as main transcript	c.3256A>G	p.Ile1086Val	missense_variant	23/39		XP_016873223.1
LRP4	XM_011520103.3 linkuse as main transcript	c.2452A>G	p.Ile818Val	missense_variant	17/32		XP_011518405.1
LRP4	XM_011520104.3 linkuse as main transcript	c.1021A>G	p.Ile341Val	missense_variant	8/23		XP_011518406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6 linkuse as main transcript	c.3256A>G	p.Ile1086Val	missense_variant	23/38	1	NM_002334.4	ENSP00000367888	P1

Frequencies

GnomAD3 genomes

AF:

0.515

AC:

78201

AN:

151806

Hom.:

23290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.208

Gnomad AMI

AF:

0.634

Gnomad AMR

AF:

0.569

Gnomad ASJ

AF:

0.734

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.668

Gnomad FIN

AF:

0.623

Gnomad MID

AF:

0.647

Gnomad NFE

AF:

0.663

Gnomad OTH

AF:

0.571

GnomAD3 exomes

AF:

0.586

AC:

147226

AN:

251342

Hom.:

46245

AF XY:

0.605

AC XY:

82120

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.731

Gnomad EAS exome

AF:

0.284

Gnomad SAS exome

AF:

0.672

Gnomad FIN exome

AF:

0.631

Gnomad NFE exome

AF:

0.672

Gnomad OTH exome

AF:

0.654

GnomAD4 exome

AF:

0.636

AC:

929801

AN:

1461214

Hom.:

303361

Cov.:

AF XY:

0.640

AC XY:

465231

AN XY:

726960

show subpopulations

Gnomad4 AFR exome

AF:

0.194

Gnomad4 AMR exome

AF:

0.501

Gnomad4 ASJ exome

AF:

0.732

Gnomad4 EAS exome

AF:

0.296

Gnomad4 SAS exome

AF:

0.662

Gnomad4 FIN exome

AF:

0.636

Gnomad4 NFE exome

AF:

0.663

Gnomad4 OTH exome

AF:

0.627

GnomAD4 genome

AF:

0.515

AC:

78217

AN:

151926

Hom.:

23301

Cov.:

AF XY:

0.515

AC XY:

38233

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.208

Gnomad4 AMR

AF:

0.569

Gnomad4 ASJ

AF:

0.734

Gnomad4 EAS

AF:

0.296

Gnomad4 SAS

AF:

0.669

Gnomad4 FIN

AF:

0.623

Gnomad4 NFE

AF:

0.663

Gnomad4 OTH

AF:

0.578

Alfa

AF:

0.647

Hom.:

78864

Bravo

AF:

0.494

TwinsUK

AF:

0.669

AC:

2479

ALSPAC

AF:

0.656

AC:

2528

ESP6500AA

AF:

0.222

AC:

977

ESP6500EA

AF:

0.667

AC:

5733

ExAC

AF:

0.585

AC:

70996

Asia WGS

AF:

0.530

AC:

1847

AN:

3478

EpiCase

AF:

0.678

EpiControl

AF:

0.683

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cenani-Lenz syndactyly syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 19079262, 23321396) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital myasthenic syndrome 17

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Sclerosteosis 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.10

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0000013

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.20

MutationTaster

Benign

0.0017

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.12

REVEL

Benign

0.22

Sift

Benign

0.81

Sift4G

Benign

0.55

Polyphen

0.0

Vest4

0.058

MPC

0.45

ClinPred

0.0017

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.42

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