5-132575886-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_005732.4(RAD50):āc.323A>Gā(p.Lys108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,611,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005732.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.323A>G | p.Lys108Arg | missense_variant | Exon 3 of 25 | 1 | NM_005732.4 | ENSP00000368100.4 | ||
ENSG00000283782 | ENST00000640655.2 | c.26A>G | p.Lys9Arg | missense_variant | Exon 4 of 26 | 5 | ENSP00000491596.2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251212Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135776
GnomAD4 exome AF: 0.0000117 AC: 17AN: 1458882Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 725982
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152364Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74508
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 108 of the RAD50 protein (p.Lys108Arg). This variant is present in population databases (rs542347773, gnomAD 0.07%). 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: 216628). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD50 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. -
Ovarian cancer Pathogenic:1
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not specified Uncertain:1
Variant summary: RAD50 c.323A>G (p.Lys108Arg) results in a conservative amino acid change located in the Rad50/SbcC-type AAA domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251212 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in RAD50 causing Nijmegen Breakage Syndrome-Like Disorder (5.6e-05 vs 0.0024), allowing no conclusion about variant significance. To our knowledge, c.323A>G has not been reported in the literature in individuals affected with Nijmegen Breakage Syndrome-Like Disorder and no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34570441, 28961279, 30982232, 36612101, 27248819, 35186721). ClinVar contains an entry for this variant (Variation ID: 216628). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Nijmegen breakage syndrome-like disorder Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at