rs1057516045

Positions:

• chr1-225403404-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_002296.4(LBR):​c.1747C>T​(p.Arg583Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000103 in 1,461,286 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: LBR NM_002296.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.65

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PP5: Variant 1-225403404-G-A is Pathogenic according to our data. Variant chr1-225403404-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 369680.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LBR	NM_002296.4	c.1747C>T	p.Arg583Ter	stop_gained	14/14	ENST00000272163.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LBR	ENST00000272163.9	c.1747C>T	p.Arg583Ter	stop_gained	14/14	1	NM_002296.4	P1
LBR	ENST00000338179.6	c.1747C>T	p.Arg583Ter	stop_gained	14/14	5		P1
LBR	ENST00000441022.1	n.222C>T		non_coding_transcript_exon_variant	2/2	2
LBR	ENST00000651341.1	c.*913C>T		3_prime_UTR_variant, NMD_transcript_variant	14/15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251442 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135888

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461286 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726980

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pelger-Huët anomaly Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 24, 2015	This nucleotide substitution results in the introduction of a premature stop codon at position 583, NP_919424.1(LBR): p.(Arg583*). This is a novel variant, not present in diseae or population databases. It is the most distal truncating variant in LBR reported to date. It segregated with phenotype in 2 members of this family. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 04, 2019	This LBR variant (rs1057516045) is rare (<0.1%) in a large population dataset (gnomAD: 4/251442 total alleles; 0.0016%; no homozygotes). Two submitters in ClinVar report this variant as likely pathogenic (Variation ID: 369680). This nonsense variant is predicted to lead to a premature stop codon in the last exon of the gene, likely escaping nonsense mediated decay and resulting in a truncated protein product. The function of the C terminal segment after the last transmembrane domain of the lamin B receptor is not known at this time. The clinical significance of c.1747C>T is uncertain at this time. -

Retrognathia;C0878659:Disproportionate short stature;C1854912:Short long bone;C1859461:Femoral bowing;C1969532:Rhizomelic arm shortening;C4023039:Rhizomelic leg shortening Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
Vest4		0.80
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1057516045; hg19: chr1-225591106; COSMIC: COSV55287340; COSMIC: COSV55287340;