rs587781940
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_005732.4(RAD50):c.3327T>G(p.Ile1109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1109V) has been classified as Uncertain significance.
Frequency
Consequence
NM_005732.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3327T>G | p.Ile1109Met | missense_variant | 21/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3327T>G | p.Ile1109Met | missense_variant | 21/25 | 1 | NM_005732.4 | P1 | |
RAD50 | ENST00000533482.5 | c.*2953T>G | 3_prime_UTR_variant, NMD_transcript_variant | 21/25 | 1 | ||||
RAD50 | ENST00000651249.1 | c.165T>G | p.Ile55Met | missense_variant | 1/6 | ||||
RAD50 | ENST00000455677.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000717 AC: 18AN: 250920Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135832
GnomAD4 exome AF: 0.000151 AC: 221AN: 1461716Hom.: 0 Cov.: 31 AF XY: 0.000143 AC XY: 104AN XY: 727154
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74360
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1109 of the RAD50 protein (p.Ile1109Met). This variant is present in population databases (rs587781940, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 141691). 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 expected to disrupt RAD50 protein function with a positive 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2023 | The p.I1109M variant (also known as c.3327T>G), located in coding exon 21 of the RAD50 gene, results from a T to G substitution at nucleotide position 3327. The isoleucine at codon 1109 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Nijmegen breakage syndrome-like disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2023 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 09, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 09, 2023 | In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)). The frequency of this variant in the general population, 0.00015 (19/129016 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at