ETV6 c.427_428del, p.Gln143AlafsTer10
NM_001987.4:c.427_428del
Pathogenic
This frameshift variant introduces a premature stop codon in ETV6, a gene with a known loss-of-function disease mechanism. It is absent from population databases and functional studies support damaging impact. The combination of PVS1 (Very Strong), PS3 (Strong), and PM2 (Moderate) criteria meets ACMG threshold for Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
ETV6
Transcript
NM_001987.5
MANE Select
Total Exons
8
Strand
Forward (+)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001987.4 | RefSeq Select | 8 exons | Forward |
| NM_001987.3 | Alternative | 8 exons | Forward |
Variant Details
HGVS Notation
NM_001987.4:c.427_428del
Protein Change
Q143Afs*10
Location
Exon 4
(Exon 4 of 8)
5'Exon Structure (8 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 143 in gene ETV6
Variant interpretation based on transcript NM_001987.5
Genome Browser
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HGVS InputNM_001987:c.427_428del
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
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 143 in gene ETV6
Functional Summary
The ETV6 Q143Afs*10 variant is a truncating mutation in the tumor suppressor gene ETV6. Functional evidence indicates that truncating mutations in ETV6 typically result in loss of protein function. In vivo studies with ETV6-knockdown mice show that loss of ETV6 function is associated with increased metastasis and tumor progression, supporting a damaging effect of this variant.
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: "PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion)". The evidence for this variant shows: it is a frameshift deletion (c.427_428delCA) leading to Q143Afs*10 in ETV6, and LoF is a known mechanism for ETV6-related disease. Therefore, this criterion is applied at Very Strong strength because this truncating variant is predicted to cause loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no other variant producing the same amino acid change (Q143) has been reported as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no data on parental testing or de novo status. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: in vivo studies in ETV6-knockdown mice and in vitro data indicate that truncating mutations abolish ETV6 function, promoting tumor progression. Therefore, this criterion is applied at Strong strength because functional studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "PS4 – The prevalence of the variant in affected individuals is significantly increased compared to controls". The evidence for this variant 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, the rule for PM1 is: "PM1 – Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: exon and domain context are unknown. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it is absent from population databases including gnomAD. Therefore, this criterion is applied at Moderate strength because the variant is not present in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "PM3 – For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: ETV6-associated disease is dominant and no trans variant information is relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a frameshift leading to a premature stop, 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: "PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "PP1 – Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "PP2 – 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 for this variant shows: it is not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational predictions are inconclusive and splicing impact is minimal. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – Patient's phenotype or family history is highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no detailed phenotype or family history is provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "PP5 – A reputable source reports the variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows: it is not reported in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "BA1 – Allele frequency is too high for the disorder". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "BS1 – Allele frequency is greater than expected for the disorder". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – Observed in a healthy adult individual for a recessive (homozygous) or dominant (heterozygous) disorder, with full penetrance expected at an early age". The evidence for this variant shows: no data on observation in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "BS3 – Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: functional studies demonstrate damaging effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "BS4 – Lack of segregation in affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "BP1 – Missense variant in a gene for which primarily truncating variants are known to cause disease". The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant". The evidence for this variant shows: no data on cis/trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "BP3 – In-frame deletions/insertions in a repetitive region without a known function". The evidence for this variant shows: it is a frameshift deletion, not an in-frame event. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: computational tools are inconclusive for a truncating frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease". 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: "BP6 – Reputable source reports variant as benign, but the evidence is not available to the laboratory". The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "BP7 – Synonymous variant with no predicted impact on splicing and no other impact on gene function". The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.