rs121913459
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_005157.6(ABL1):c.944C>T(p.Thr315Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,association (★★).
Frequency
Consequence
NM_005157.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABL1 | ENST00000318560.6 | c.944C>T | p.Thr315Ile | missense_variant | Exon 6 of 11 | 1 | NM_005157.6 | ENSP00000323315.5 | ||
ABL1 | ENST00000372348.9 | c.1001C>T | p.Thr334Ile | missense_variant | Exon 6 of 11 | 1 | ENSP00000361423.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Chronic myelogenous leukemia, BCR-ABL1 positive Pathogenic:1Other:1
ABL1, a tyrosine kinase, is frequently altered by chromosomal translocations in leukemia. The BCR-ABL1 fusion is known to be oncogenic. The ABL1 T315I is a known resistance mutation. Diagnostic Summary: The presence of a BCR-ABL1 fusion is consistent with the diagnosis of chronic myeloid leukemia. Therapeutic Summary: The presence of the BCR-ABL1 fusion in myeloproliferative neoplasms is diagnostic of chronic myelogenous leukemia (CML). The NCCN considers the ABL1 T315I mutation as "contraindicated" for the therapies imatinib, dasatinib, nilotinib, and bosutinib in patients with BCR-ABL1 positive (+) CML. The multikinase inhibitor ponatinib and the BCR-ABL1 inhibitor asciminib are FDA approved for adult patients with ABL1 T315I+ BCRABL1 fusion+ CML. -
Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with ABL1 related disorder (ClinVar ID: VCV000012624). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (ClinVar ID: VCV000376118). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Leukemia, Philadelphia chromosome-positive, resistant to imatinib Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at