rs144953114
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS1
The NM_006265.3(RAD21):āc.1352T>Gā(p.Leu451Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,610,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00033 ( 0 hom., cov: 32)
Exomes š: 0.00052 ( 0 hom. )
Consequence
RAD21
NM_006265.3 missense
NM_006265.3 missense
Scores
4
8
7
Clinical Significance
Conservation
PhyloP100: 8.89
Genes affected
RAD21 (HGNC:9811): (RAD21 cohesin complex component) The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad21, a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis. This protein is a nuclear phospho-protein, which becomes hyperphosphorylated in cell cycle M phase. The highly regulated association of this protein with mitotic chromatin specifically at the centromere region suggests its role in sister chromatid cohesion in mitotic cells. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAD21. . Gene score misZ 2.6421 (greater than the threshold 3.09). Trascript score misZ 3.6451 (greater than threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 4, Mungan syndrome.
BP6
Variant 8-116852066-A-C is Benign according to our data. Variant chr8-116852066-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372619.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr8-116852066-A-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000335 (51/152300) while in subpopulation NFE AF= 0.000573 (39/68020). AF 95% confidence interval is 0.000431. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAD21 | NM_006265.3 | c.1352T>G | p.Leu451Arg | missense_variant | 11/14 | ENST00000297338.7 | NP_006256.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD21 | ENST00000297338.7 | c.1352T>G | p.Leu451Arg | missense_variant | 11/14 | 1 | NM_006265.3 | ENSP00000297338 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000283 AC: 71AN: 250940Hom.: 0 AF XY: 0.000288 AC XY: 39AN XY: 135616
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GnomAD4 exome AF: 0.000525 AC: 765AN: 1458322Hom.: 0 Cov.: 31 AF XY: 0.000501 AC XY: 363AN XY: 724872
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GnomAD4 genome AF: 0.000335 AC: 51AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74464
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 451 of the RAD21 protein (p.Leu451Arg). This variant is present in population databases (rs144953114, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RAD21-related conditions. ClinVar contains an entry for this variant (Variation ID: 372619). 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 not expected to disrupt RAD21 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Mungan syndrome;C3553517:Cornelia de Lange syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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