Classification rationale

PM2 BP7 VUS

ABL1 c.908-16G>A

The ABL1 c.908-16G>A (p.?) variant has been reported in ClinVar as likely benign with single-submitter review status.¹ This variant is present at very low frequency in population databases, with allele frequencies of 0.00082% in gnomAD v2.1 and 0.00169% in gnomAD v4.1, both below the 0.1% PM2 threshold used in this workflow.² SpliceAI predicts no significant splice effect for this intronic change, with a maximum delta score of 0.01, which supports a benign computational interpretation.³

PM2 + BP7 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_005157.4 · variants mapped to exon structure

ABL1 NM_005157.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is rare in population databases. In gnomAD v2.1 the allele frequency is 0.00082% (2/244756), and in gnomAD v4.1 the allele frequency is 0.00169% (27/1600974), both below the 0.1% threshold used for PM2 in this workflow.

gnomAD v2.1 AF 8.1714e-06gnomAD v4.1 AF 1.68647e-05

gnomad_v2 ↗gnomad_v4 ↗

BP7 supporting Benign

This intronic variant is located at c.908-16, outside the canonical splice region, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01. These findings support BP7.

Intronic position c.908-16SpliceAI max delta score 0.01

spliceai ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PVS1 ABL1 loss of function is considered an eligible disease mechanism in the generic PVS1 gate, but this variant is intronic at c.908-16, is outside the canonical +/-1,2 splice sites, and does not fall into the generic null-variant buckets for PVS1.

PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant.

PS3 No well-established functional study or RNA assay was identified for this exact variant, so PS3 cannot be applied.

PS4 No case-control enrichment or multiple independent affected observations were identified for this variant.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype information was available to determine whether the clinical presentation is highly specific for a disease caused by ABL1.

Benign

BA1 The population frequency does not meet the BA1 benign stand-alone threshold.

BS1 The population frequency does not reach the BS1 threshold.

BS2 No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2.

BS3 No well-established functional study showing no damaging effect was identified for this variant.

BS4 No non-segregation data were identified for this variant.

BP2 No phase data were identified to determine whether this variant occurs in cis or in trans with another variant.

BP5 No alternate molecular explanation was identified for an observed phenotype, so BP5 was not assessed.

N/A · 11 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP4 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.68647e-05; MAF= 0.00169%, 27/1600974 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.22007e-05; MAF= 0.00222%, 26/1171134 alleles, homozygotes = 0); grpmax FAF= 1.544e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.1714e-06; MAF= 0.00082%, 2/244756 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.372e-05; MAF= 0.00337%, 1/29656 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0017% · 27 / 1,600,974
0 hom · FAF 0.0015%

European (non-Finnish) 26 / 1,171,134	0.0022%
South Asian 1 / 90,118	0.0011%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00082% · 2 / 244,756
0 hom

South Asian 1 / 29,656	0.0034%
European (non-Finnish) 1 / 110,438	0.00091%

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

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 4763580)

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

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Triaged references · 1 PMID not cited in assessment

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

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