9-130885248-A-G

Position:

• chr9-130885248-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005157.6(ABL1):​c.2958A>G​(p.Pro986=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,828 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (31 hom.)
• Consequence: ABL1 NM_005157.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-130885248-A-G is Benign according to our data. Variant chr9-130885248-A-G is described in ClinVar as [Benign]. Clinvar id is 786778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00139 (211/152294) while in subpopulation EAS AF= 0.0302 (156/5174). AF 95% confidence interval is 0.0263. There are 2 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABL1	NM_005157.6	c.2958A>G	p.Pro986=	synonymous_variant	11/11	ENST00000318560.6	NP_005148.2
ABL1	NM_007313.3	c.3015A>G	p.Pro1005=	synonymous_variant	11/11		NP_009297.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000318560.6	c.2958A>G	p.Pro986=	synonymous_variant	11/11	1	NM_005157.6	ENSP00000323315
ABL1	ENST00000372348.9	c.3015A>G	p.Pro1005=	synonymous_variant	11/11	1		ENSP00000361423	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0303

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00371 AC: 930 AN: 250786 Hom.: 11 AF XY: 0.00321 AC XY: 436 AN XY: 135702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00821

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.0285

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00149 AC: 2181 AN: 1461534 Hom.: 31 Cov.: 32 AF XY: 0.00144 AC XY: 1047 AN XY: 727098

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00738

Gnomad4 ASJ exome AF: 0.00291

Gnomad4 EAS exome AF: 0.0350

Gnomad4 SAS exome AF: 0.00194

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152294 Hom.: 2 Cov.: 33 AF XY: 0.00168 AC XY: 125 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.0302

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000651 Hom.: 0

Bravo AF: 0.00215

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.016
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs35445683; hg19: chr9-133760635; COSMIC: COSV59325759;