rs144953114
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). Synonymous variant affecting the same amino acid position (i.e. L451L) has been classified as Likely benign.
Frequency
Consequence
NM_006265.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD21 | NM_006265.3 | c.1352T>G | p.Leu451Arg | missense_variant | 11/14 | ENST00000297338.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD21 | ENST00000297338.7 | c.1352T>G | p.Leu451Arg | missense_variant | 11/14 | 1 | NM_006265.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000283 AC: 71AN: 250940Hom.: 0 AF XY: 0.000288 AC XY: 39AN XY: 135616
GnomAD4 exome AF: 0.000525 AC: 765AN: 1458322Hom.: 0 Cov.: 31 AF XY: 0.000501 AC XY: 363AN XY: 724872
GnomAD4 genome AF: 0.000335 AC: 51AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74464
ClinVar
Submissions by phenotype
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 | - - |
Cornelia de Lange syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | 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. - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at