rs200180113

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002296.4(LBR):c.1114C>T(p.Arg372Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,772 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R372H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

LBR
NM_002296.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

LBR (HGNC:6518): (lamin B receptor) The protein encoded by this gene belongs to the ERG4/ERG24 family. It localized in the nuclear envelope inner membrane and anchors the lamina and the heterochromatin to the membrane. It may mediate interaction between chromatin and lamin B. Mutations of this gene has been associated with autosomal recessive HEM/Greenberg skeletal dysplasia. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

LBR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LBR	NM_002296.4 linkuse as main transcript	c.1114C>T	p.Arg372Cys	missense_variant	9/14	ENST00000272163.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LBR	ENST00000272163.9 linkuse as main transcript	c.1114C>T	p.Arg372Cys	missense_variant	9/14	1	NM_002296.4	P1
LBR	ENST00000338179.6 linkuse as main transcript	c.1114C>T	p.Arg372Cys	missense_variant	9/14	5		P1
LBR	ENST00000424022.2 linkuse as main transcript	n.7C>T		non_coding_transcript_exon_variant	1/3	3
LBR	ENST00000651341.1 linkuse as main transcript	c.1114C>T	p.Arg372Cys	missense_variant, NMD_transcript_variant	9/15

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000254

AC:

AN:

251478

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000248

AC:

362

AN:

1461448

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.000281

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000210

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Reynolds syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 372 of the LBR protein (p.Arg372Cys). This variant is present in population databases (rs200180113, gnomAD 0.04%). This missense change has been observed in individual(s) with Reynolds syndrome (PMID: 20522425). ClinVar contains an entry for this variant (Variation ID: 9533). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LBR protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LBR function (PMID: 20522425). 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. -

Greenberg dysplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.55

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.97

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H

MutationTaster

Benign

1.0

A;A

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.69

MVP

0.93

MPC

0.57

ClinPred

0.53

GERP RS

6.2

Varity_R

0.73

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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