9-130714339-A-G

Position:

• chr9-130714339-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The ENST00000372348.9(ABL1):​c.20A>G​(p.Lys7Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ABL1 ENST00000372348.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.38

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 Likely_benign. Variant got -3 ACMG points.

• 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 4.3141 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart defects and skeletal malformations syndrome, connective tissue disorder.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABL1	NM_007313.3	c.20A>G	p.Lys7Arg	missense_variant	1/11		NP_009297.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000372348.9	c.20A>G	p.Lys7Arg	missense_variant	1/11	1		ENSP00000361423	P1
ABL1	ENST00000393293.4	c.20A>G	p.Lys7Arg	missense_variant	1/2	5		ENSP00000376971

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249498 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458634 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2021

The c.20A>G (p.K7R) alteration is located in exon 1 (coding exon 1) of the ABL1 gene. This alteration results from a A to G substitution at nucleotide position 20, causing the lysine (K) at amino acid position 7 to be replaced by an arginine (R). The p.K7R alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2022

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 not expected to disrupt ABL1 protein function. This variant has not been reported in the literature in individuals affected with ABL1-related conditions. This variant is present in population databases (rs375730000, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 7 of the ABL1 protein (p.Lys7Arg). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.60	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.26	T;D
Sift4G	Benign	0.78	T;D
Vest4		0.45
MVP		0.86
MPC		0.64
ClinPred		0.92	D
GERP RS		5.6
gMVP		0.62

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: rs375730000; hg19: chr9-133589726;