1-225419442-C-T

Position:

chr1-225419442-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 Benign. Variant got -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 id is 258619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225419442-C-T is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LBR	NM_002296.4 linkuse as main transcript	c.461G>A	p.Ser154Asn	missense_variant	5/14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LBR	ENST00000272163.9 linkuse as main transcript	c.461G>A	p.Ser154Asn	missense_variant	5/14	1	NM_002296.4	ENSP00000272163	P1
LBR	ENST00000338179.6 linkuse as main transcript	c.461G>A	p.Ser154Asn	missense_variant	5/14	5		ENSP00000339883	P1
LBR	ENST00000425080.1 linkuse as main transcript	c.461G>A	p.Ser154Asn	missense_variant	5/5	3		ENSP00000388059
LBR	ENST00000651341.1 linkuse as main transcript	c.461G>A	p.Ser154Asn	missense_variant, NMD_transcript_variant	5/15			ENSP00000499114

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

GnomAD3 exomes

AF:

0.811

AC:

202788

AN:

249900

Hom.:

84223

AF XY:

0.810

AC XY:

109600

AN XY:

135252

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 SAS exome

AF:

0.699

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

Gnomad4 AFR exome

AF:

0.411

Gnomad4 AMR exome

AF:

0.869

Gnomad4 ASJ exome

AF:

0.889

Gnomad4 EAS exome

AF:

0.962

Gnomad4 SAS exome

AF:

0.698

Gnomad4 FIN exome

AF:

0.858

Gnomad4 NFE exome

AF:

0.837

Gnomad4 OTH exome

AF:

0.825

GnomAD4 genome

AF:

0.729

AC:

110989

AN:

152148

Hom.:

43287

Cov.:

AF XY:

0.732

AC XY:

54406

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.428

Gnomad4 AMR

AF:

0.850

Gnomad4 ASJ

AF:

0.887

Gnomad4 EAS

AF:

0.957

Gnomad4 SAS

AF:

0.698

Gnomad4 FIN

AF:

0.862

Gnomad4 NFE

AF:

0.840

Gnomad4 OTH

AF:

0.785

Alfa

AF:

0.831

Hom.:

115315

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

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 80% of total chromosomes in ExAC -

Greenberg dysplasia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Reynolds syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Pelger-Huët anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.015

DANN

Benign

0.38

DEOGEN2

Benign

0.32

T;T;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.056

.;T;T

MetaRNN

Benign

9.9e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

0.090

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.56

T;T;T

Sift4G

Benign

0.54

T;T;.

Polyphen

0.014

B;B;B

Vest4

0.015

MPC

0.094

ClinPred

0.010

GERP RS

-8.0

Varity_R

0.030

gMVP

0.13

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