rs1060499548

Variant names:

• chr9-130872961-G-A
• rs1060499548
• NM_005157.6:c.1009G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_005157.6(ABL1):​c.1009G>A​(p.Ala337Thr) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABL1 NM_005157.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• PP5: Variant 9-130872961-G-A is Pathogenic according to our data. Variant chr9-130872961-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 374794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABL1	NM_005157.6	c.1009G>A	p.Ala337Thr	missense_variant	Exon 6 of 11	ENST00000318560.6	NP_005148.2
ABL1	NM_007313.3	c.1066G>A	p.Ala356Thr	missense_variant	Exon 6 of 11		NP_009297.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000318560.6	c.1009G>A	p.Ala337Thr	missense_variant	Exon 6 of 11	1	NM_005157.6	ENSP00000323315.5
ABL1	ENST00000372348.9	c.1066G>A	p.Ala356Thr	missense_variant	Exon 6 of 11	1		ENSP00000361423.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital heart defects and skeletal malformations syndrome Pathogenic:3

Jan 01, 2020

Human Development and Health, University of Southampton

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

- -

Oct 31, 2023

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant in exon 6 of the ABL1 gene that results in the amino acid substitution of Threonine for Alanine at codon 337 (p.Ala337Thr) was detected. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv), and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

Nov 11, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Aug 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with threonine at codon 356 of the ABL1 protein (p.Ala356Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABL1 function (PMID: 28288113). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABL1 protein function. ClinVar contains an entry for this variant (Variation ID: 374794). This missense change has been observed in individual(s) with congenital heart defects and skeletal malformations syndrome (PMID: 28288113, 32643838). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). -

Jul 03, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A356T pathogenic variant in the ABL1 gene has been reported previously as a de novo variant in an individual with features of ABL1-related disorder (Wang et al., 2017). The A356T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A356T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies indicate that the A356T variant is associated with increased tyrosine phosphorylation (Wang et al., 2017). We interpret A356T as a pathogenic variant. -

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

Dec 11, 2016

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was seen once in our laboratory de novo in a 1-year-old male with IUGR, atrial septal defect, diaphragmatic hernia, microcephaly, failure to thrive, dysmorphic features, short stature, pectus excavatum, 2-3 toe syndactyly, imperforate anus, unilateral undescended testicle. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	.;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.28	.;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	.;D
Vest4		0.91
MutPred		0.48		.;Loss of stability (P = 0.1329);
MVP		0.86
MPC		2.3
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.74
gMVP		0.73

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: rs1060499548; hg19: chr9-133748348;