chr5-132616119-G-A
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_005732.4(RAD50):c.3153G>A(p.Leu1051Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,612,792 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_005732.4 synonymous
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3153G>A | p.Leu1051Leu | synonymous_variant | Exon 20 of 25 | 1 | NM_005732.4 | ENSP00000368100.4 | ||
ENSG00000283782 | ENST00000640655.2 | c.2856G>A | p.Leu952Leu | synonymous_variant | Exon 21 of 26 | 5 | ENSP00000491596.2 |
Frequencies
GnomAD3 genomes AF: 0.00302 AC: 459AN: 152186Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.000770 AC: 193AN: 250768Hom.: 1 AF XY: 0.000524 AC XY: 71AN XY: 135578
GnomAD4 exome AF: 0.000330 AC: 482AN: 1460488Hom.: 1 Cov.: 31 AF XY: 0.000289 AC XY: 210AN XY: 726580
GnomAD4 genome AF: 0.00307 AC: 468AN: 152304Hom.: 4 Cov.: 32 AF XY: 0.00307 AC XY: 229AN XY: 74482
ClinVar
Submissions by phenotype
not specified Benign:2
Variant summary: RAD50 c.3153G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.001 in 276550 control chromosomes, predominantly at a frequency of 0.011 within the African subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 175.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Co-occurrences with other potentially pathogenic variant(s) have been reported (RAD50 c.552-1G>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
- -
Hereditary cancer-predisposing syndrome Benign:2
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. -
- -
Nijmegen breakage syndrome-like disorder Benign:2
- -
- -
not provided Benign:1
- -
Familial cancer of breast Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at