rs1060499547

Positions:

• chr9-130862890-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_005157.6(ABL1):​c.677A>G​(p.Tyr226Cys) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABL1 NM_005157.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.32

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 15 ACMG points.

• PM1: In a modified_residue Phosphotyrosine; by autocatalysis (size 0) in uniprot entity ABL1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.874
• PP5: Variant 9-130862890-A-G is Pathogenic according to our data. Variant chr9-130862890-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374795.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.677A>G	p.Tyr226Cys	missense_variant	4/11	ENST00000318560.6	NP_005148.2
ABL1	NM_007313.3	c.734A>G	p.Tyr245Cys	missense_variant	4/11		NP_009297.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000318560.6	c.677A>G	p.Tyr226Cys	missense_variant	4/11	1	NM_005157.6	ENSP00000323315.5
ABL1	ENST00000372348.9	c.734A>G	p.Tyr245Cys	missense_variant	4/11	1		ENSP00000361423.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital heart defects and skeletal malformations syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 02, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 22, 2022	- -

Congenital heart disease;C2315100:Failure to thrive;C4023165:Abnormal skeletal morphology Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 11, 2016

This variant has been found four times in our laboratory in individuals with heart defects, skeletal anomalies, and failure to thrive. In two families, it co-segregated with disease, and it arose de novo in a third. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2021

Published functional studies demonstrate that this variant leads to a gain of function with increased ABL kinase activity (Wang et al., 2017); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28288113) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.9	.;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.36		.;Loss of phosphorylation at Y226 (P = 0.0123);
MVP		0.92
MPC		2.6
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.86

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: rs1060499547; hg19: chr9-133738277;