Variant classification summary

NM_005157.4:c.908-16G>A

ABL1 · NP_005148.2:p.? · NM_005157.4

GRCh37: chr9:133748231 G>A · GRCh38: chr9:130872844 G>A

Gene: ABL1 Transcript: NM_005157.4

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

ABL1

Transcript

NM_005157.4

Protein

NP_005148.2:p.?

gnomAD AF

1.6864733593425003e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ABL1 c.908-16G>A (p.?) variant has been reported in ClinVar as likely benign with single-submitter review status.

2

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.

3

SpliceAI predicts no significant splice effect for this intronic change, with a maximum delta score of 0.01, which supports a benign computational interpretation.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	Not met	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. SpliceAI also predicts no significant splice impact (max delta score 0.01), so current evidence does not support PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	This criterion applies to a different nucleotide change causing the same amino acid substitution. This intronic variant has no defined amino acid change, so PS1 is not applicable.
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study or RNA assay was identified for this exact variant, so PS3 cannot be applied.	clinvar spliceai
PS4	Not assessed	No case-control enrichment or multiple independent affected observations were identified for this variant.	clinvar gnomad_v2 gnomad_v4
PM1	N/A	PM1 is used for variants in a critical functional domain or mutational hot spot without benign variation. This intronic variant does not map to a protein residue or domain, so PM1 is not applicable.
PM2	Met	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 gnomad_v4
PM3	N/A	PM3 applies to recessive disease with pathogenic variants observed in trans. No recessive trans data were identified for this variant, and this criterion is not applicable here.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This intronic single-nucleotide variant does not have that effect.
PM5	N/A	PM5 uses same-residue missense comparator logic. This variant is intronic with no amino acid residue context, and the PM5 candidate review did not support classic PM5 use.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	N/A	PP2 applies to missense variants in genes with low benign missense variation and a pathogenic missense mechanism. This intronic variant is not a missense change.
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and no REVEL, BayesDel, or HCI prior result was available for this intronic variant.	spliceai
PP4	Not assessed	No phenotype information was available to determine whether the clinical presentation is highly specific for a disease caused by ABL1.
PP5	N/A	PP5 was not used because current ACMG/AMP practice does not rely on an external assertion alone as evidence for pathogenicity.	clinvar
BA1	Not met	The population frequency does not meet the BA1 benign stand-alone threshold. The highest observed overall frequency is 0.00169% in gnomAD v4.1, which is below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The population frequency does not reach the BS1 threshold. The highest observed overall frequency is 0.00169% in gnomAD v4.1, which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing no damaging effect was identified for this variant.	spliceai
BS4	Not assessed	No non-segregation data were identified for this variant.	clinvar
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are primarily pathogenic. This intronic variant is not a missense change.
BP2	Not assessed	No phase data were identified to determine whether this variant occurs in cis or in trans with another variant.
BP3	N/A	BP3 applies to in-frame variants in repetitive regions without known function. This intronic single-nucleotide variant does not fit that criterion.
BP4	N/A	For this intronic variant, benign computational splice evidence is captured more specifically under BP7. BP4 was not applied separately to avoid double counting the same in silico evidence.	spliceai
BP5	Not assessed	No alternate molecular explanation was identified for an observed phenotype, so BP5 was not assessed.
BP6	N/A	BP6 was not used because current ACMG/AMP practice does not rely on an external assertion alone as evidence for benignity.	clinvar
BP7	Met	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.	spliceai

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