chr9-130872896-CT-TC

Variant names:

• chr9-130872896-CT-TC
• NM_005157.6:c.944_945delCTinsTC
• ABL1 p.Thr315Ile

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM2

The NM_005157.6(ABL1):c.944_945delCTinsTC (p.Thr315Ile) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. 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: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Pathogenic. The variant received 10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	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.

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.944_945delCTinsTC p.Thr315Ile	missense	N/A	Prot: NP_005148.2 UniProt:
	ABL1 NM_007313.3		c.1001_1002delCTinsTC p.Thr334Ile	missense	N/A	Prot: NP_009297.2 UniProt:

ABL1 NM_005157.6

MANE Select

HGVSc / HGVSpc.944_945delCTinsTCp.Thr315Ile

Exon rankN/A

missense

Prot: NP_005148.2UniProt: P00519-1

ABL1 NM_007313.3

HGVSc / HGVSpc.1001_1002delCTinsTCp.Thr334Ile

Exon rankN/A

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.944_945delCTinsTC p.Thr315Ile	missense	N/A	Prot: ENSP00000323315.5 UniProt:
	ABL1 ENST00000372348.9	TSL:1	c.1001_1002delCTinsTC p.Thr334Ile	missense	N/A	Prot: ENSP00000361423.2 UniProt:
	ABL1 ENST00000929254.1		c.941_942delCTinsTC p.Thr314Ile	missense	N/A	Prot: ENSP00000599313.1 UniProt:

ABL1 ENST00000318560.6

TSL:1MANE Select

HGVSc / HGVSpc.944_945delCTinsTCp.Thr315Ile

Exon rankN/A

missense

Prot: ENSP00000323315.5UniProt: P00519-1

ABL1 ENST00000372348.9

TSL:1

HGVSc / HGVSpc.1001_1002delCTinsTCp.Thr334Ile

Exon rankN/A

missense

Prot: ENSP00000361423.2UniProt: P00519-2

ABL1 ENST00000929254.1

HGVSc / HGVSpc.941_942delCTinsTCp.Thr314Ile

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr9-133748283;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar