Variant classification summary

NM_001987.4:c.329-15C>A

ETV6 · NP_001978.1:p.? · NM_001987.4

GRCh37: chr12:12006346 C>A · GRCh38: chr12:11853412 C>A

Gene: ETV6 Transcript: NM_001987.4

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign

Variant details

Gene

ETV6

Transcript

NM_001987.4

Protein

NP_001978.1:p.?

gnomAD AF

5.638613223353525e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001987.4:c.329-15C>A is an intronic substitution in ETV6 (intron 3, c.329-15) with no predicted splicing impact (SpliceAI max delta 0.01).

2

This variant is present in gnomAD at very low frequency (v2.1: 14/282,700 alleles, AF=0.00495%; v4.1: 91/1,613,872 alleles, AF=0.00564%) with no homozygotes observed.

3

ClinVar reports this variant as Likely benign by Labcorp Genetics/Invitae (ClinVarID 1908625, SCV002946987), with criteria provided.

4

In silico evidence supports a benign interpretation: SpliceAI predicts no splicing alteration, and no computational tool suggests a deleterious effect.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are 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	Intronic variant at c.329-15 position in ETV6 intron 3; not a null variant (nonsense, frameshift, canonical ±1,2 splice). PVS1 is not applicable to non-null intronic variants under the generic PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	Intronic variant; not a missense change at an amino acid residue with a known pathogenic missense variant. PS1 requires same amino acid change as an established pathogenic variant.
PS2	Not assessed	No de novo observation data for NM_001987.4:c.329-15C>A identified in ClinVar, literature, or any evidence source.
PS3	Not assessed	No well-established functional studies evaluating the biological effect of NM_001987.4:c.329-15C>A were identified. SpliceAI (max delta 0.01) is an in silico predictor, not a functional assay, and is considered under BP4.
PS4	Not assessed	No case-control or cohort studies reporting NM_001987.4:c.329-15C>A prevalence in affected individuals were identified. The sole associated publication (PMID:28492532) is a methodology paper describing the Sherloc classification framework and does not report variant-specific patient observations.
PS5	N/A	ClinVar reports this variant as Likely benign (single submitter, Labcorp/Invitae). PS5 requires a reputable source asserting pathogenicity; a benign classification does not satisfy PS5.	clinvar
PM1	N/A	No mutational hotspot or functional domain enrichment data for NM_001987.4:c.329-15C>A. The variant lies in intron 3, not in a well-characterized functional domain with established pathogenic missense enrichment.
PM2	Met	NM_001987.4:c.329-15C>A is present in gnomAD at extremely low frequency: AF=0.00495% (14/282,700 alleles) in v2.1 and AF=0.00564% (91/1,613,872 alleles) in v4.1, with no homozygotes observed. The allele frequency is well below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4
PM5	N/A	Intronic variant at c.329-15; no amino acid change. PM5 requires a different missense change at the same residue as a known pathogenic missense variant and does not apply to intronic substitutions.
PM6	Not assessed	No de novo observation with unconfirmed or confirmed parentage identified for NM_001987.4:c.329-15C>A in ClinVar or literature.
PP1	Not assessed	No co-segregation data available for NM_001987.4:c.329-15C>A. No family studies or pedigrees were identified in ClinVar or literature.
PP2	N/A	Intronic variant; not a missense change. PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score 0.01). REVEL and BayesDel are not applicable to this intronic variant. HCI prior is not available for ETV6. No computational evidence supports pathogenicity.	spliceai
PP4	Not assessed	No phenotype specificity data available for NM_001987.4:c.329-15C>A. No patient phenotype descriptions specific to this variant were found in ClinVar submissions or literature.
PP5	N/A	ClinVar reports this variant as Likely benign (single submitter, Labcorp/Invitae). PP5 requires a reputable source asserting pathogenicity; a benign classification does not satisfy PP5.	clinvar
BA1	Not met	NM_001987.4:c.329-15C>A has an allele frequency of ~0.005% in gnomAD, well below the 1% threshold required for BA1 (stand-alone benign).	gnomad_v2 gnomad_v4
BS1	Not met	NM_001987.4:c.329-15C>A has an allele frequency of ~0.005% in gnomAD, well below the 0.3% threshold for BS1 (strong benign population frequency).	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on trans or cis configurations with pathogenic variants available for NM_001987.4:c.329-15C>A. While the variant is observed in gnomAD (a predominantly healthy population cohort), the traditional BS2 criterion requires observation in trans with a dominant pathogenic variant or in cis with a pathogenic variant.
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect of NM_001987.4:c.329-15C>A were identified. SpliceAI prediction is an in silico tool addressed under BP4.
BS4	Not assessed	No segregation data available to evaluate lack of segregation with disease for NM_001987.4:c.329-15C>A.
BP1	N/A	Intronic variant; not a missense change. BP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease.
BP2	Not assessed	No data on observation in trans with a dominant pathogenic variant or in cis with a pathogenic variant for NM_001987.4:c.329-15C>A.
BP3	N/A	This is a substitution, not an in-frame indel in a non-repeat region. BP3 does not apply.
BP4	Met	Multiple lines of in silico evidence predict no impact. SpliceAI predicts no significant splicing alteration (max delta score 0.01, well below the 0.02 threshold). REVEL and BayesDel are not applicable to this intronic variant. The SpliceAI result supports a benign interpretation.	spliceai
BP5	Not assessed	No alternative molecular cause was identified to explain the phenotype. BP5 requires observation of a molecular basis for disease in a case where the variant in question is also present.
BP6	Met	ClinVar reports this variant as Likely benign by a clinical testing laboratory (Labcorp Genetics, formerly Invitae) with criteria provided (ClinVarID 1908625, SCV002946987). This constitutes a reputable source supporting a benign classification.	clinvar
BP7	N/A	NM_001987.4:c.329-15C>A is an intronic variant, not a synonymous (silent) variant. BP7 applies to synonymous variants with no predicted splice impact.

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