Classification rationale

PM2 BP4BP6 Likely Benign

ETV6 c.329-15C>A

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).¹ 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.² ClinVar reports this variant as Likely benign by Labcorp Genetics/Invitae (ClinVarID 1908625, SCV002946987), with criteria provided.³ In silico evidence supports a benign interpretation: SpliceAI predicts no splicing alteration, and no computational tool suggests a deleterious effect.⁴

PM2 + BP4 + BP6 → Likely Benign

1 spliceai ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 clinvar ↗

4 spliceai ↗

Gene diagram · NM_001987.4 · variants mapped to exon structure

ETV6 NM_001987.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 14 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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 v2.1: 14/282700 allelesAF=4.95e-05 (0.00495%)

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

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 max delta score: 0.01 (acceptor gainacceptor lossdonor gain

spliceai ↗

✓

BP6 supporting Benign

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 classification: Likely benigncriteria providedsingle submitter (Labcorp/Invitae)

clinvar ↗

Assessed · not applied

Pathogenic

PS2 No de novo observation data for NM_001987.4:c.329-15C>A identified in ClinVar, literature, or any evidence source.

PS3 No well-established functional studies evaluating the biological effect of NM_001987.4:c.329-15C>A were identified.

PS4 No case-control or cohort studies reporting NM_001987.4:c.329-15C>A prevalence in affected individuals were identified.

PM6 No de novo observation with unconfirmed or confirmed parentage identified for NM_001987.4:c.329-15C>A in ClinVar or literature.

PP1 No co-segregation data available for NM_001987.4:c.329-15C>A.

PP3 Multiple lines of in silico evidence do not support a deleterious effect.

PP4 No phenotype specificity data available for NM_001987.4:c.329-15C>A.

Benign

BA1 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).

BS1 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).

BS2 No data on trans or cis configurations with pathogenic variants available for NM_001987.4:c.329-15C>A.

BS3 No well-established functional studies demonstrating no deleterious effect of NM_001987.4:c.329-15C>A were identified.

BS4 No segregation data available to evaluate lack of segregation with disease for NM_001987.4:c.329-15C>A.

BP2 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.

BP5 No alternative molecular cause was identified to explain the phenotype.

N/A · 9 PVS1 · PS1 · PM1 · PM5 · PP2 · PP5 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.63861e-05; MAF= 0.00564%, 91/1613872 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.45801e-05; MAF= 0.00746%, 88/1179940 alleles, homozygotes = 0); grpmax FAF= 6.146e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.95225e-05; MAF= 0.00495%, 14/282700 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000100658; MAF= 0.01007%, 13/129150 alleles, homozygotes = 0); grpmax FAF= 5.378e-05.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0056% · 91 / 1,613,872
0 hom · FAF 0.0061%

European (non-Finnish) 88 / 1,179,940	0.0075%
Remaining individuals 2 / 62,474	0.0032%
African/African American 1 / 74,900	0.0013%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.005% · 14 / 282,700
0 hom · FAF 0.0054%

European (non-Finnish) 13 / 129,150	0.01%
African/African American 1 / 24,956	0.004%

+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1908625)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 1 PMID not cited in assessment

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?