chr11-46868614-C-T

Position:

chr11-46868614-C-T

Variant summary

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

The NM_002334.4(LRP4):c.4937G>A(p.Arg1646Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 1,612,518 control chromosomes in the GnomAD database, including 437,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 33083 hom., cov: 31)

Exomes 𝑓: 0.74 ( 404028 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.35

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:):

LRP4-AS1 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=9.1250956E-7).

BP6

Variant 11-46868614-C-T is Benign according to our data. Variant chr11-46868614-C-T is described in ClinVar as [Benign]. Clinvar id is 304850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46868614-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP4	NM_002334.4 linkuse as main transcript	c.4937G>A	p.Arg1646Gln	missense_variant	33/38	ENST00000378623.6	NP_002325.2	O75096

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRP4	ENST00000378623.6 linkuse as main transcript	c.4937G>A	p.Arg1646Gln	missense_variant	33/38	1	NM_002334.4	ENSP00000367888.1	O75096
LRP4-AS1	ENST00000502049.3 linkuse as main transcript	n.193-4460C>T		intron_variant		2
LRP4-AS1	ENST00000531719.5 linkuse as main transcript	n.292-4460C>T		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.642

AC:

97579

AN:

151964

Hom.:

33070

Cov.:

show subpopulations

Gnomad AFR

AF:

0.429

Gnomad AMI

AF:

0.746

Gnomad AMR

AF:

0.655

Gnomad ASJ

AF:

0.810

Gnomad EAS

AF:

0.394

Gnomad SAS

AF:

0.725

Gnomad FIN

AF:

0.674

Gnomad MID

AF:

0.712

Gnomad NFE

AF:

0.765

Gnomad OTH

AF:

0.683

GnomAD3 exomes

AF:

0.679

AC:

170284

AN:

250940

Hom.:

60422

AF XY:

0.694

AC XY:

94151

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.428

Gnomad AMR exome

AF:

0.537

Gnomad ASJ exome

AF:

0.807

Gnomad EAS exome

AF:

0.377

Gnomad SAS exome

AF:

0.735

Gnomad FIN exome

AF:

0.683

Gnomad NFE exome

AF:

0.776

Gnomad OTH exome

AF:

0.744

GnomAD4 exome

AF:

0.738

AC:

1077370

AN:

1460436

Hom.:

404028

Cov.:

AF XY:

0.740

AC XY:

537487

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.417

Gnomad4 AMR exome

AF:

0.554

Gnomad4 ASJ exome

AF:

0.810

Gnomad4 EAS exome

AF:

0.381

Gnomad4 SAS exome

AF:

0.729

Gnomad4 FIN exome

AF:

0.692

Gnomad4 NFE exome

AF:

0.769

Gnomad4 OTH exome

AF:

0.730

GnomAD4 genome

AF:

0.642

AC:

97611

AN:

152082

Hom.:

33083

Cov.:

AF XY:

0.637

AC XY:

47355

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.429

Gnomad4 AMR

AF:

0.655

Gnomad4 ASJ

AF:

0.810

Gnomad4 EAS

AF:

0.393

Gnomad4 SAS

AF:

0.725

Gnomad4 FIN

AF:

0.674

Gnomad4 NFE

AF:

0.765

Gnomad4 OTH

AF:

0.689

Alfa

AF:

0.749

Hom.:

92930

Bravo

AF:

0.629

TwinsUK

AF:

0.780

AC:

2892

ALSPAC

AF:

0.759

AC:

2927

ESP6500AA

AF:

0.442

AC:

1947

ESP6500EA

AF:

0.772

AC:

6634

ExAC

AF:

0.684

AC:

83070

Asia WGS

AF:

0.620

AC:

2157

AN:

3478

EpiCase

AF:

0.776

EpiControl

AF:

0.783

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 06, 2018	- -
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

0.075

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.73

MetaRNN

Benign

9.1e-7

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.45

REVEL

Benign

0.25

Sift

Benign

0.20

Sift4G

Benign

0.57

Polyphen

0.0050

Vest4

0.055

MPC

0.64

ClinPred

0.0065

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.020

gMVP

0.71

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