9-130872896-C-T

Position:

• chr9-130872896-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000318560.6(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T315A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABL1 ENST00000318560.6 missense
• Clinical Significance: Likely pathogenic; association criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.91

Genes affected

ABL1 (HGNC:76): (ABL proto-oncogene 1, non-receptor tyrosine kinase) This gene is a protooncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of the protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene. The ubiquitously expressed protein has DNA-binding activity that is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function. This gene has been found fused to a variety of translocation partner genes in various leukemias, most notably the t(9;22) translocation that results in a fusion with the 5' end of the breakpoint cluster region gene (BCR; MIM:151410). Alternative splicing of this gene results in two transcript variants, which contain alternative first exons that are spliced to the remaining common exons. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000318560.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-130872895-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376118.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABL1. . Gene score misZ 2.5581 (greater than the threshold 3.09). Trascript score misZ 4.2755 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart defects and skeletal malformations syndrome, connective tissue disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 9-130872896-C-T is Pathogenic according to our data. Variant chr9-130872896-C-T is described in ClinVar as [Likely_pathogenic, association]. Clinvar id is 12624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABL1	NM_005157.6	c.944C>T	p.Thr315Ile	missense_variant	6/11	ENST00000318560.6	NP_005148.2
ABL1	NM_007313.3	c.1001C>T	p.Thr334Ile	missense_variant	6/11		NP_009297.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000318560.6	c.944C>T	p.Thr315Ile	missense_variant	6/11	1	NM_005157.6	ENSP00000323315
ABL1	ENST00000372348.9	c.1001C>T	p.Thr334Ile	missense_variant	6/11	1		ENSP00000361423	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic; association

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chronic myelogenous leukemia, BCR-ABL1 positive Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -
association, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Sep 13, 2023	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. -

Leukemia, Philadelphia chromosome-positive, resistant to imatinib Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.95
MutPred		0.65		.;Loss of sheet (P = 0.302);
MVP		0.93
MPC		2.4
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.89
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121913459; hg19: chr9-133748283; COSMIC: COSV59323790;