rs573510559

Positions:

chr1-225403394-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5PP3_StrongPP5

The NM_002296.4(LBR):c.1757G>A(p.Arg586His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,088 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R586C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

LBR
NM_002296.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

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 7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-225403395-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1320971.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 1-225403394-C-T is Pathogenic according to our data. Variant chr1-225403394-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 545626.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LBR	NM_002296.4 linkuse as main transcript	c.1757G>A	p.Arg586His	missense_variant	14/14	ENST00000272163.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LBR	ENST00000272163.9 linkuse as main transcript	c.1757G>A	p.Arg586His	missense_variant	14/14	1	NM_002296.4	P1
LBR	ENST00000338179.6 linkuse as main transcript	c.1757G>A	p.Arg586His	missense_variant	14/14	5		P1
LBR	ENST00000441022.1 linkuse as main transcript	n.232G>A		non_coding_transcript_exon_variant	2/2	2
LBR	ENST00000651341.1 linkuse as main transcript	c.*923G>A		3_prime_UTR_variant, NMD_transcript_variant	14/15

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

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:

0.0000358

AC:

AN:

251460

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461506

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151582

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73964

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Regressive spondylometaphyseal dysplasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 03, 2022

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 586 of the LBR protein (p.Arg586His). This variant is present in population databases (rs573510559, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive LBR-related conditions (PMID: 23824842, 34567078, 36307859). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 545626). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LBR protein function with a positive predictive value of 80%. This variant disrupts the p.Arg586 amino acid residue in LBR. Other variant(s) that disrupt this residue have been observed in individuals with LBR-related conditions (PMID: 30448303), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Greenberg dysplasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province

Aug 28, 2022

- -

Pelger-Huët anomaly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Mar 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.3

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.93

Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);

MVP

0.93

MPC

0.57

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.91

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