rs121913459

Variant names:

• chr9-130872896-C-T
• rs121913459
• NM_005157.6:c.944C>T
• ABL1 p.Thr315Ile

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM2PP5_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 is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABL1 NM_005157.6 missense
• Clinical Significance: Likely pathogenic; association criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.91
• Publications: 2995 publications found

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]

ABL1 Gene-Disease associations (from GenCC):

• congenital heart defects and skeletal malformations syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• bone development disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005157.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ABL1 NM_005157.6	MANE Select	c.944C>T p.Thr315Ile	missense	Exon 6 of 11	Prot: NP_005148.2 UniProt:
	ABL1 NM_007313.3		c.1001C>T p.Thr334Ile	missense	Exon 6 of 11	Prot: NP_009297.2 UniProt:

ABL1 NM_005157.6

MANE Select

HGVSc / HGVSpc.944C>Tp.Thr315Ile

Exon rankExon 6 of 11

missense

Prot: NP_005148.2UniProt: P00519-1

ABL1 NM_007313.3

HGVSc / HGVSpc.1001C>Tp.Thr334Ile

Exon rankExon 6 of 11

missense

Prot: NP_009297.2UniProt: P00519-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ABL1 ENST00000318560.6	TSL:1MANE Select	c.944C>T p.Thr315Ile	missense	Exon 6 of 11	Prot: ENSP00000323315.5 UniProt:
	ABL1 ENST00000372348.9	TSL:1	c.1001C>T p.Thr334Ile	missense	Exon 6 of 11	Prot: ENSP00000361423.2 UniProt:
	ABL1 ENST00000929254.1		c.941C>T p.Thr314Ile	missense	Exon 6 of 11	Prot: ENSP00000599313.1 UniProt:

ABL1 ENST00000318560.6

TSL:1MANE Select

HGVSc / HGVSpc.944C>Tp.Thr315Ile

Exon rankExon 6 of 11

missense

Prot: ENSP00000323315.5UniProt: P00519-1

ABL1 ENST00000372348.9

TSL:1

HGVSc / HGVSpc.1001C>Tp.Thr334Ile

Exon rankExon 6 of 11

missense

Prot: ENSP00000361423.2UniProt: P00519-2

ABL1 ENST00000929254.1

HGVSc / HGVSpc.941C>Tp.Thr314Ile

Exon rankExon 6 of 11

missense

Prot: ENSP00000599313.1UniProt: A0ACI8THP2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:202868	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	48254	0.0000269	2	74252

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely pathogenic; association

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Chronic myeloid leukemia (2)
1	-	-	Leukemia, Philadelphia chromosome-positive, resistant to imatinib (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
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
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-8.9
GPN-Star score	N/A	8.9
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.42	T
Mutation Taster	N/A	3/97	disease causing (ClinVar)
MutationAssessor	Benign	1.8	L
PhyloP100	Pathogenic	7.9
popEVE	Benign	-4.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.89
VESM-3B	Benign	-12

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121913459;

hg19: chr9-133748283;

COSMIC: COSV59323790;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar