rs1057516045
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_StrongPP5
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
NM_002296.4 stop_gained
Scores
5
1
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 genomes
?
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32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251442Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461286Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 726980
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Pelger-Huët anomaly Pathogenic:1Uncertain: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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at