RAD21 c.836A>T, p.Asp279Val
NM_006265.2:c.836A>T
Variant of Uncertain Significance (VUS)
This RAD21 missense variant is absent from population databases (PM2) and computational predictions suggest benign impact (BP4), with no additional supporting or conflicting evidence; thus classified as Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
RAD21
Transcript
NM_006265.3
MANE Select
Total Exons
14
Strand
Reverse (−)
Reference Sequence
NC_000008.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006265.2 | RefSeq Select | 14 exons | Reverse |
| NM_006265.1 | Alternative | 14 exons | Reverse |
Variant Details
HGVS Notation
NM_006265.2:c.836A>T
Protein Change
D279V
Location
Exon 8
(Exon 8 of 14)
5'Exon Structure (14 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 279 in gene RAD21
Variant interpretation based on transcript NM_006265.3
Genome Browser
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HGVS InputNM_006265:c.836A>T
Active Tracks
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 279 in gene RAD21
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.113
0.113
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
Benign:
CADD: 4.32metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines for PVS1, the rule is: 'Null variant in a gene where loss of function is a known mechanism of disease'. The evidence shows: this variant is a missense change (D279V), not predicted to create a null allele. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS1, the rule is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence shows: no known pathogenic variant at amino acid position D279. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS2, the rule is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence shows: no de novo testing or pedigree information available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS3, the rule is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence shows: no functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS4, the rule is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence shows: no case-control or cohort data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM1, the rule is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence shows: position D279 is not reported as a mutational hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines for PM2, the rule is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence shows: variant not found in population databases including gnomAD (MAF=0%). Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM3, the rule is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence shows: no evidence of trans configuration or recessive inheritance. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM4, the rule is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence shows: this is a missense variant without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM5, the rule is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence shows: no other pathogenic missense changes reported at D279. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM6, the rule is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence shows: no parental data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP1, the rule is: 'Co-segregation with disease in multiple affected family members'. The evidence shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP2, the rule is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence shows: insufficient data on RAD21 missense constraint. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP3, the rule is: 'Multiple lines of computational evidence support a deleterious effect'. The evidence shows: computational predictions are conflicting (REVEL 0.11 suggests benign, PolyPhen suggests damaging). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP4, the rule is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence shows: no phenotype information provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP5, the rule is: 'Reputable source reports variant as pathogenic but without accessible evidence'. The evidence shows: variant not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines for BA1, the rule is: 'Allele frequency is too high for the disorder'. The evidence shows: variant absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines for BS1, the rule is: 'Allele frequency is greater than expected for disorder'. The evidence shows: variant absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines for BS2, the rule is: 'Observed in healthy individual(s) for dominant disorder with full penetrance expected at an early age'. The evidence shows: no observation in healthy individuals reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines for BS3, the rule is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence shows: no functional assay data available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines for BS4, the rule is: 'Lack of segregation in affected family members'. The evidence shows: no family studies available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP1, the rule is: 'Missense variant in a gene where only loss of function causes disease'. The evidence shows: disease mechanism for RAD21 includes haploinsufficiency but missense variants also reported. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP2, the rule is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence shows: no data on phase with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP3, the rule is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence shows: this is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines for BP4, the rule is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence shows: REVEL score 0.11 below threshold, SpliceAI shows no splicing impact, other in silico tools support benign. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP5, the rule is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence shows: no reports of alternate molecular etiologies. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP6, the rule is: 'Reputable source reports variant as benign but without accessible evidence'. The evidence shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP7, the rule is: 'Synonymous variant with no predicted impact on splicing'. The evidence shows: this is a missense variant, not synonymous. Therefore, this criterion is not applied.