9-130854076-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_005157.6(ABL1):c.92G>A(p.Arg31Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,612,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: ABL1 NM_005157.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.27

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ABL1
• BP4: Computational evidence support a benign effect (MetaRNN=0.13868684).
• BP6: Variant 9-130854076-G-A is Benign according to our data. Variant chr9-130854076-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1589007.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABL1	NM_005157.6	c.92G>A	p.Arg31Gln	missense_variant	2/11	ENST00000318560.6
ABL1	NM_007313.3	c.149G>A	p.Arg50Gln	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABL1	ENST00000318560.6	c.92G>A	p.Arg31Gln	missense_variant	2/11	1	NM_005157.6
ABL1	ENST00000372348.9	c.149G>A	p.Arg50Gln	missense_variant	2/11	1		P1
ABL1	ENST00000393293.4	c.146G>A	p.Arg49Gln	missense_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.0000659 AC: 10 AN: 151792 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000880 AC: 22 AN: 249976 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135126

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000592

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1460470 Hom.: 0 Cov.: 30 AF XY: 0.0000661 AC XY: 48 AN XY: 726484

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000465

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000659 AC: 10 AN: 151792 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74074

Gnomad4 AFR AF: 0.0000726

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000969 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N;D;N
REVEL	Benign	0.16
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.94	.;.;P
Vest4		0.35
MVP		0.41
MPC		0.79
ClinPred		0.51	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs368476764; hg19: chr9-133729463;