rs587777172

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_002296.4(LBR):c.1748G>T(p.Arg583Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LBR
NM_002296.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.78

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 Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 1-225403403-C-A is Pathogenic according to our data. Variant chr1-225403403-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 419545.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LBR	NM_002296.4 linkuse as main transcript	c.1748G>T	p.Arg583Leu	missense_variant	14/14	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.1748G>T	p.Arg583Leu	missense_variant	14/14	1	NM_002296.4	ENSP00000272163	P1
LBR	ENST00000338179.6 linkuse as main transcript	c.1748G>T	p.Arg583Leu	missense_variant	14/14	5		ENSP00000339883	P1
LBR	ENST00000441022.1 linkuse as main transcript	n.223G>T		non_coding_transcript_exon_variant	2/2	2
LBR	ENST00000651341.1 linkuse as main transcript	c.*914G>T		3_prime_UTR_variant, NMD_transcript_variant	14/15			ENSP00000499114

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251440

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461488

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151740

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74066

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2015

The R583L substitution in the LBR gene has not been reported previously as a pathogenic variant noras a benign polymorphism, to our knowledge. However, a different amino acid substitution at this residue(R583Q) has been reported in the compound heterozygous state in an individual with Greenberg dysplasia(Clayton et al., 2010). The R583L substitution was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The R583L variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is conserved across species.In silico analysis predicts this variant is probably damaging to the protein structure/function. A missensevariant in a nearby residue (R586H) has been reported in the Human Gene Mutation Database inassociation with Pelger-Huet anomaly (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. We interpret R583L as a pathogenic variant. -

RHIZOMELIC SKELETAL DYSPLASIA WITH PELGER-HUET ANOMALY

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.95

Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);

MVP

0.97

MPC

0.57

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.50

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.50

Position offset: -3

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