chr9-130854093-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005157.6(ABL1):ā€‹c.109T>Gā€‹(p.Phe37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

ABL1
NM_005157.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.14804545).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABL1NM_005157.6 linkuse as main transcriptc.109T>G p.Phe37Val missense_variant 2/11 ENST00000318560.6 NP_005148.2
ABL1NM_007313.3 linkuse as main transcriptc.166T>G p.Phe56Val missense_variant 2/11 NP_009297.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABL1ENST00000318560.6 linkuse as main transcriptc.109T>G p.Phe37Val missense_variant 2/111 NM_005157.6 ENSP00000323315 P00519-1
ABL1ENST00000372348.9 linkuse as main transcriptc.166T>G p.Phe56Val missense_variant 2/111 ENSP00000361423 P1P00519-2
ABL1ENST00000393293.4 linkuse as main transcriptc.163T>G p.Phe55Val missense_variant 2/25 ENSP00000376971

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461810
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152326
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 24, 2021In 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. 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 sequence change replaces phenylalanine with valine at codon 56 of the ABL1 protein (p.Phe56Val). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ABL1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Uncertain
0.040
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.13
.;T;T
Eigen
Benign
-0.22
Eigen_PC
Benign
0.011
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.54
T;T;T
M_CAP
Benign
0.0064
T
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
.;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.33
N;D;N
REVEL
Benign
0.21
Sift
Benign
0.56
T;D;T
Sift4G
Benign
0.62
T;D;T
Polyphen
0.021
.;.;B
Vest4
0.28
MutPred
0.19
.;.;Gain of catalytic residue at F37 (P = 0.1294);
MVP
0.74
MPC
0.29
ClinPred
0.58
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.13
gMVP
0.39

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1830934244; hg19: chr9-133729480; API