Variant classification summary

NM_001987.4:c.642G>A

ETV6 · NP_001978.1:p.(Pro214=) · NM_001987.4

GRCh37: chr12:12022536 G>A · GRCh38: chr12:11869602 G>A

Gene: ETV6 Transcript: NM_001987.4

Final call

Benign

BA1 stand-alone benign BP7 supporting

Variant details

Gene

ETV6

Transcript

NM_001987.4

Protein

NP_001978.1:p.(Pro214=)

gnomAD AF

0.0011889022572415238 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (Stand-alone Benign): gnomAD v4.1 African/African American allele frequency 2.13033% (1598/75012 alleles, 21 homozygotes) exceeds the 1% BA1 threshold.

2

BP7 (Supporting): synonymous variant (p.(Pro214=)) with no predicted splice impact (SpliceAI max delta 0.003).

3

Overall classification: Benign — BA1 at stand-alone strength under generic ACMG/AMP 2015 combination rules (no ETV6 VCEP available), with no pathogenic-direction criteria met.

Final determination: Under the generic ACMG/AMP 2015 fallback, a single stand-alone benign criterion (BA1) is sufficient by itself to classify a variant as Benign, regardless of additional supporting benign evidence (BP7) also present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: this is a synonymous (silent) variant, so no null-variant mechanism such as nonsense-mediated decay or truncation applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: a synonymous variant produces no amino acid change (p.(Pro214=)) to compare against a previously pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available.
PS3	Not assessed	Not assessed: no validated functional assay for this variant was available; SpliceAI (max delta 0.00) is only a computational prediction.
PS4	Not assessed	Not assessed: no variant-specific case-control or statistical enrichment data were available.
PM1	N/A	Not applicable: a synonymous variant creates no altered residue to evaluate for mutational hot-spot or critical-domain membership.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 African/African American allele frequency 2.13033% shows the variant is far too common for PM2 rarity.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband data pair this variant with a pathogenic ETV6 variant in trans.	PMID:25741868
PM4	N/A	Not applicable: a synonymous variant causes no change in protein length for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental genotypes or de novo testing result was provided.
PP1	Not assessed	Not assessed: no pedigree, relative genotypes, or informative meioses were provided for segregation analysis.
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-constraint properties are irrelevant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: synonymous variant with no predicted splice impact (SpliceAI max delta 0.003) and no missense change for in-silico scoring.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or testing indication was supplied to assess a specific ETV6-associated phenotype.
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic assertion exists for this exact variant.	clinvar
BA1	Met	Met (stand-alone benign): gnomAD v4.1 African/African American allele frequency 2.13033% (1598/75012 alleles) exceeds the 1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	N/A	Not applicable: BA1 already applies the same population-frequency evidence, so BS1 is not additionally applied.	gnomad_v4
BS2	Not assessed	Not assessed: population datasets lack phenotype, age, and disease-status data for individual carriers.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no validated functional assay of this variant was found; SpliceAI max delta 0.00 is computational only.
BS4	Not assessed	Not assessed: no family data show lack of segregation between this variant and a relevant phenotype.
BP1	N/A	Not applicable: no missense change is present, so the gene's truncating-disease mechanism is irrelevant here.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no co-occurrence or phase observation was available.	PMID:25741868
BP3	N/A	Not applicable: a synonymous variant does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: benign splice prediction routes synonymous variants through BP7; BP4 is reserved for missense in-silico evidence.	spliceai
BP5	Not assessed	Not assessed: no evidence of an alternate molecular diagnosis explaining the reported phenotype was available.
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign assertion exists for this exact variant.	clinvar
BP7	Met	Met (supporting): synonymous variant with SpliceAI max delta 0.003, indicating no predicted splice impact.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.