NM_002296.4:c.461G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002296.4(LBR):c.461G>A(p.Ser154Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 1,609,378 control chromosomes in the GnomAD database, including 543,983 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 43287 hom., cov: 33)

Exomes 𝑓: 0.82 ( 500696 hom. )

Consequence

LBR
NM_002296.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.167

Publications

42 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

LBR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.891029E-7).

BP6

Variant 1-225419442-C-T is Benign according to our data. Variant chr1-225419442-C-T is described in ClinVar as Benign. ClinVar VariationId is 258619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002296.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LBR	NM_002296.4	MANE Select	c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	NP_002287.2
	LBR	NM_194442.3		c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	NP_919424.1	Q14739

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LBR	ENST00000272163.9	TSL:1 MANE Select	c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	ENSP00000272163.4	Q14739
LBR	ENST00000338179.6	TSL:5	c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	ENSP00000339883.2	Q14739
LBR	ENST00000885795.1		c.461G>A	p.Ser154Asn	missense	Exon 5 of 14	ENSP00000555854.1

Frequencies

GnomAD3 genomes

AF:

0.730

AC:

110920

AN:

152030

Hom.:

43266

Cov.:

show subpopulations

Gnomad AFR

AF:

0.428

Gnomad AMI

AF:

0.752

Gnomad AMR

AF:

0.849

Gnomad ASJ

AF:

0.887

Gnomad EAS

AF:

0.957

Gnomad SAS

AF:

0.698

Gnomad FIN

AF:

0.862

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.840

Gnomad OTH

AF:

0.781

GnomAD2 exomes

AF:

0.811

AC:

202788

AN:

249900

AF XY:

0.810

show subpopulations

Gnomad AFR exome

AF:

0.419

Gnomad AMR exome

AF:

0.872

Gnomad ASJ exome

AF:

0.891

Gnomad EAS exome

AF:

0.958

Gnomad FIN exome

AF:

0.855

Gnomad NFE exome

AF:

0.838

Gnomad OTH exome

AF:

0.850

GnomAD4 exome

AF:

0.825

AC:

1202186

AN:

1457230

Hom.:

500696

Cov.:

AF XY:

0.822

AC XY:

596356

AN XY:

725214

show subpopulations

African (AFR)

AF:

0.411

AC:

13705

AN:

33386

American (AMR)

AF:

0.869

AC:

38793

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.889

AC:

23204

AN:

26104

East Asian (EAS)

AF:

0.962

AC:

38185

AN:

39688

South Asian (SAS)

AF:

0.698

AC:

60009

AN:

86030

European-Finnish (FIN)

AF:

0.858

AC:

45803

AN:

53376

Middle Eastern (MID)

AF:

0.864

AC:

4914

AN:

5686

European-Non Finnish (NFE)

AF:

0.837

AC:

927851

AN:

1108056

Other (OTH)

AF:

0.825

AC:

49722

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

9363

18727

28090

37454

46817

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20862

41724

62586

83448

104310

<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:

0.729

AC:

110989

AN:

152148

Hom.:

43287

Cov.:

AF XY:

0.732

AC XY:

54406

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.428

AC:

17743

AN:

41460

American (AMR)

AF:

0.850

AC:

12995

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.887

AC:

3079

AN:

3470

East Asian (EAS)

AF:

0.957

AC:

4957

AN:

5180

South Asian (SAS)

AF:

0.698

AC:

3369

AN:

4824

European-Finnish (FIN)

AF:

0.862

AC:

9138

AN:

10602

Middle Eastern (MID)

AF:

0.888

AC:

261

AN:

294

European-Non Finnish (NFE)

AF:

0.840

AC:

57102

AN:

67998

Other (OTH)

AF:

0.785

AC:

1659

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1281

2561

3842

5122

6403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

818

1636

2454

3272

4090

<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:

0.812

Hom.:

219363

Bravo

AF:

0.718

TwinsUK

AF:

0.830

AC:

3077

ALSPAC

AF:

0.840

AC:

3238

ESP6500AA

AF:

0.437

AC:

1926

ESP6500EA

AF:

0.840

AC:

7221

ExAC

AF:

0.799

AC:

97048

Asia WGS

AF:

0.823

AC:

2862

AN:

3478

EpiCase

AF:

0.844

EpiControl

AF:

0.846

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Greenberg dysplasia (2)

not specified (2)

Pelger-Huët anomaly (1)

Reynolds syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.015

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.32

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.056

MetaRNN

Benign

9.9e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.17

PrimateAI

Benign

0.28

PROVEAN

Benign

0.090

REVEL

Benign

0.17

Sift

Benign

0.56

Sift4G

Benign

0.54

Polyphen

0.014

Vest4

0.015

MPC

0.094

ClinPred

0.010

GERP RS

-8.0

Varity_R

0.030

gMVP

0.13

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over