rs200180113

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PP3_ModeratePP5BS1_SupportingBS2

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:3

Conservation

PhyloP100: 7.90

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

Greenberg dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Pelger-Huet anomaly
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
regressive spondylometaphyseal dysplasia
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

LBR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

PP5

Variant 1-225411411-G-A is Pathogenic according to our data. Variant chr1-225411411-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9533.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00021 (32/152324) while in subpopulation NFE AF = 0.000338 (23/68036). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBR	NM_002296.4 link	c.1114C>T	p.Arg372Cys	missense_variant	Exon 9 of 14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LBR	ENST00000272163.9 link	c.1114C>T	p.Arg372Cys	missense_variant	Exon 9 of 14	1	NM_002296.4	ENSP00000272163.4
LBR	ENST00000338179.6 link	c.1114C>T	p.Arg372Cys	missense_variant	Exon 9 of 14	5		ENSP00000339883.2
LBR	ENST00000424022.2 link	n.7C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3
LBR	ENST00000651341.1 link	n.1114C>T		non_coding_transcript_exon_variant	Exon 9 of 15			ENSP00000499114.1

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

GnomAD2 exomes

AF:

0.000254

AC:

AN:

251478

AF XY:

0.000258

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 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

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.000128

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000243

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000281

AC:

312

AN:

1111616

Other (OTH)

AF:

0.000232

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000210

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41564

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000384

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:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Reynolds syndrome

Pathogenic:2

Jun 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence 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 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;C4747922:Regressive spondylometaphyseal dysplasia

Uncertain:1

Jan 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Greenberg dysplasia

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H

PhyloP100

7.9

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

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over