Genetic Variant LMNB1:p.Arg10Leu (chr5-126777537-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005573.4(LMNB1):c.29G>T(p.Arg10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,413,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

LMNB1
NM_005573.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.59

Variant links:

Genes affected

LMNB1 (HGNC:6637): (lamin B1) This gene encodes one of the two B-type lamin proteins and is a component of the nuclear lamina. A duplication of this gene is associated with autosomal dominant adult-onset leukodystrophy (ADLD). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

LMNB1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005152911).

BP6

Variant 5-126777537-G-T is Benign according to our data. Variant chr5-126777537-G-T is described in ClinVar as [Benign]. Clinvar id is 1563912.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-126777537-G-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 142 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNB1	NM_005573.4 link	c.29G>T	p.Arg10Leu	missense_variant	Exon 1 of 11	ENST00000261366.10	NP_005564.1	P20700
LMNB1	NM_001198557.2 link	c.-272+293G>T		intron_variant	Intron 1 of 10		NP_001185486.1	B4DZT3
LMNB1	NR_134488.1 link	n.915G>T		non_coding_transcript_exon_variant	Exon 1 of 12
LMNB1	NR_177109.1 link	n.402G>T		non_coding_transcript_exon_variant	Exon 1 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNB1	ENST00000261366.10 link	c.29G>T	p.Arg10Leu	missense_variant	Exon 1 of 11	1	NM_005573.4	ENSP00000261366.5		P20700

Frequencies

GnomAD3 genomes

AF:

0.000934

AC:

142

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

58784

Hom.:

AF XY:

0.000204

AC XY:

AN XY:

34294

show subpopulations

Gnomad AFR exome

AF:

0.00702

Gnomad AMR exome

AF:

0.000883

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

154

AN:

1261466

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

617238

show subpopulations

Gnomad4 AFR exome

AF:

0.00428

Gnomad4 AMR exome

AF:

0.000480

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000188

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000933

AC:

142

AN:

152214

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00330

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000491

Hom.:

Bravo

AF:

0.00110

ExAC

AF:

0.000163

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

LMNB1-related disorder

Benign:1

Aug 14, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Uncertain

0.70

D;T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.9

L;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.3

N;.;N

REVEL

Benign

0.28

Sift

Uncertain

0.0060

D;.;D

Sift4G

Benign

0.37

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.36

MutPred

0.25

Loss of MoRF binding (P = 0.0168);Loss of MoRF binding (P = 0.0168);Loss of MoRF binding (P = 0.0168);

MVP

0.83

MPC

0.65

ClinPred

0.049

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.23

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