RAD21 c.943_946del, p.Glu315GlnfsTer9
NM_006265.2:c.943_946del
Pathogenic
This frameshift variant (E315Qfs*9) introduces a premature stop leading to loss of function in RAD21, a gene where LoF is a known mechanism of disease. The variant is absent in population databases, supported by functional studies demonstrating damaging effect, and reported as pathogenic in ClinVar, fulfilling PVS1, PS3, PM2, and PP5 and supporting a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
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.943_946del
Protein Change
E315Qfs*9
Location
Exon 9
(Exon 9 of 14)
5'Exon Structure (14 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 315 in gene RAD21
Variant interpretation based on transcript NM_006265.3
Genome Browser
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HGVS InputNM_006265:c.943_946del
Active Tracks
ConservationRefSeqClinVargnomAD
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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
1 publications
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1185049). This premature translational stop signal has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 30716475, 32193685). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu315Glnfs*9) in the RAD21 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD21 are known to be pathogenic (PMID: 22633399, 24378232, 27620904, 27882533).
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories).
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 315 in gene RAD21
Functional Summary
The RAD21 E315Qfs*9 variant is a truncating mutation that likely results in loss of function. Functional studies indicate that truncating mutations in RAD21 are associated with significantly reduced RAD21 expression and defective chromosomal separation due to impaired cohesion complex function. This variant is implicated in oncogenesis, particularly in myeloid malignancies, where it occurs as a late event in leukemia development.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (Very Strong Evidence)". The evidence for this variant shows: c.943_946delGAAA results in a frameshift and premature stop (E315Qfs*9) in RAD21, predicted to cause loss of function. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a gene where LoF is established as the mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change (Strong Evidence)". The evidence for this variant shows: no known pathogenic variant produces the same amino acid change by a different nucleotide alteration. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history (Strong Evidence)". The evidence for this variant shows: no data on de novo occurrence with confirmed parentage. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product (Strong Evidence)". The evidence for this variant shows: functional studies demonstrate that truncating RAD21 variants, including E315Qfs*9, reduce RAD21 expression and impair cohesion complex function. Therefore, this criterion is applied at Strong strength because in vitro/in vivo studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls (Strong Evidence)". The evidence for this variant shows: no data on case-control enrichment or statistical prevalence. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation (Moderate Evidence)". The evidence for this variant shows: domain or hotspot information is unavailable for the affected region. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) (Moderate Evidence)". The evidence for this variant shows: not present in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders (Moderate Evidence)". The evidence for this variant shows: RAD21-related disease is autosomal dominant and no trans observations are provided. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants (Moderate Evidence)". The evidence for this variant shows: this is a frameshift leading to premature termination, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen (Moderate Evidence)". The evidence for this variant shows: it is not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity (Moderate Evidence)". The evidence for this variant shows: no de novo data provided. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members (Supporting Evidence)". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease (Supporting Evidence)". The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product (Supporting Evidence)". The evidence for this variant shows: computational splicing analysis indicates minimal impact, and as a frameshift the result is LoF. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology (Supporting Evidence)". The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence (Supporting Evidence)". The evidence for this variant shows: ClinVar lists this variant as Pathogenic (1 clinical laboratory) without accessible primary data. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (Stand-alone Benign)". The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder (Strong Benign)". The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age (Strong Benign)". The evidence for this variant shows: no observations in healthy individuals reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing (Strong Benign)". The evidence for this variant shows: functional studies indicate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members (Strong Benign)". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease (Supporting Benign)". The evidence for this variant shows: it is a LoF variant, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant (Supporting Benign)". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function (Supporting Benign)". The evidence for this variant shows: it is a frameshift outside of repetitive context. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (Supporting Benign)". The evidence for this variant shows: computational splicing analysis indicates minimal effect, but the variant is a frameshift causing LoF. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease (Supporting Benign)". The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence (Supporting Benign)". The evidence for this variant shows: no reputable source reports benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing (Supporting Benign)". The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.