rs118009068

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_002334.4(LRP4):c.1117C>T(p.Arg373Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,613,888 control chromosomes in the GnomAD database, including 427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 24 hom., cov: 33)

Exomes 𝑓: 0.022 ( 403 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.41

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=0.011091918).

BP6

Variant 11-46895950-G-A is Benign according to our data. Variant chr11-46895950-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 304890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46895950-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2598/152290) while in subpopulation NFE AF= 0.026 (1766/68024). AF 95% confidence interval is 0.025. There are 24 homozygotes in gnomad4. There are 1236 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP4	NM_002334.4 linkuse as main transcript	c.1117C>T	p.Arg373Trp	missense_variant	10/38	ENST00000378623.6	NP_002325.2	O75096
LRP4	XM_017017734.2 linkuse as main transcript	c.1117C>T	p.Arg373Trp	missense_variant	10/39		XP_016873223.1
LRP4	XM_011520103.3 linkuse as main transcript	c.313C>T	p.Arg105Trp	missense_variant	4/32		XP_011518405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6 linkuse as main transcript	c.1117C>T	p.Arg373Trp	missense_variant	10/38	1	NM_002334.4	ENSP00000367888.1		O75096

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2603

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00526

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0164

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0203

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0260

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0183

AC:

4599

AN:

251196

Hom.:

AF XY:

0.0194

AC XY:

2631

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0285

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0174

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0258

Gnomad OTH exome

AF:

0.0230

GnomAD4 exome

AF:

0.0219

AC:

31976

AN:

1461598

Hom.:

403

Cov.:

AF XY:

0.0219

AC XY:

15920

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00385

Gnomad4 AMR exome

AF:

0.0118

Gnomad4 ASJ exome

AF:

0.0269

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0176

Gnomad4 FIN exome

AF:

0.0139

Gnomad4 NFE exome

AF:

0.0243

Gnomad4 OTH exome

AF:

0.0201

GnomAD4 genome

AF:

0.0171

AC:

2598

AN:

152290

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1236

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00524

Gnomad4 AMR

AF:

0.0164

Gnomad4 ASJ

AF:

0.0228

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.0124

Gnomad4 NFE

AF:

0.0260

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.0230

Hom.:

Bravo

AF:

0.0162

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0241

AC:

ESP6500AA

AF:

0.00591

AC:

ESP6500EA

AF:

0.0273

AC:

235

ExAC

AF:

0.0187

AC:

2275

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0268

EpiControl

AF:

0.0268

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2020	This variant is associated with the following publications: (PMID: 30327840) -

Cenani-Lenz syndactyly syndrome

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.095

MutationAssessor

Benign

0.31

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.63

Sift

Benign

0.050

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.31

MPC

1.5

ClinPred

0.012

GERP RS

4.9

Varity_R

0.27

gMVP

0.56

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