rs80299691
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_002296.4(LBR):āc.1609T>Gā(p.Ser537Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000893 in 1,613,984 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0041 ( 2 hom., cov: 32)
Exomes š: 0.00056 ( 7 hom. )
Consequence
LBR
NM_002296.4 missense
NM_002296.4 missense
Scores
1
12
4
Clinical Significance
Conservation
PhyloP100: 4.15
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.022507876).
BP6
?
Variant 1-225404482-A-C is Benign according to our data. Variant chr1-225404482-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235704.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=2, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00414 (630/152352) while in subpopulation AFR AF= 0.0145 (601/41572). AF 95% confidence interval is 0.0135. There are 2 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LBR | NM_002296.4 | c.1609T>G | p.Ser537Ala | missense_variant | 13/14 | ENST00000272163.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LBR | ENST00000272163.9 | c.1609T>G | p.Ser537Ala | missense_variant | 13/14 | 1 | NM_002296.4 | P1 | |
LBR | ENST00000338179.6 | c.1609T>G | p.Ser537Ala | missense_variant | 13/14 | 5 | P1 | ||
LBR | ENST00000441022.1 | n.84T>G | non_coding_transcript_exon_variant | 1/2 | 2 | ||||
LBR | ENST00000651341.1 | c.*775T>G | 3_prime_UTR_variant, NMD_transcript_variant | 13/15 |
Frequencies
GnomAD3 genomes ? AF: 0.00413 AC: 629AN: 152234Hom.: 2 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00124 AC: 311AN: 251354Hom.: 0 AF XY: 0.000854 AC XY: 116AN XY: 135852
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GnomAD4 exome AF: 0.000556 AC: 812AN: 1461632Hom.: 7 Cov.: 31 AF XY: 0.000490 AC XY: 356AN XY: 727144
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GnomAD4 genome ? AF: 0.00414 AC: 630AN: 152352Hom.: 2 Cov.: 32 AF XY: 0.00404 AC XY: 301AN XY: 74500
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ESP6500AA
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ExAC
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Asia WGS
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3478
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 21, 2017 | This variant has not been reported in individuals with skeletal dysplasia (rs80299691). The p.Ser537Ala variant is listed in the Genome Aggregation Consortium browser with an allele frequency of 1.62 percent (identified on 390 out of 24,030 chromosomes, including 1 homozygote) in the African populations and with an overall allele frequency of 0.15 percent (identified on 426 out of 277,154 chromosomes, including 1 homozygote). It has been reported to ClinVar (Variation ID 235704). - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 12, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 05, 2018 | - - |
Connective tissue disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 28, 2020 | - - |
Greenberg dysplasia Benign:1
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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.31
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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