rs34549764

Positions:

• chr9-130862953-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000318560.6(ABL1):​c.740A>G​(p.Lys247Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,614,194 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (13 hom.)
• Consequence: ABL1 ENST00000318560.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 7.47

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 -17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000318560.6
• 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=0.0153794885).
• BP6: Variant 9-130862953-A-G is Benign according to our data. Variant chr9-130862953-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 133450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130862953-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00248 (378/152304) while in subpopulation NFE AF= 0.00432 (294/68020). AF 95% confidence interval is 0.00392. There are 1 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABL1	NM_005157.6	c.740A>G	p.Lys247Arg	missense_variant	4/11	ENST00000318560.6	NP_005148.2
ABL1	NM_007313.3	c.797A>G	p.Lys266Arg	missense_variant	4/11		NP_009297.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000318560.6	c.740A>G	p.Lys247Arg	missense_variant	4/11	1	NM_005157.6	ENSP00000323315
ABL1	ENST00000372348.9	c.797A>G	p.Lys266Arg	missense_variant	4/11	1		ENSP00000361423	P1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00432

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00258 AC: 649 AN: 251116 Hom.: 2 AF XY: 0.00248 AC XY: 336 AN XY: 135754

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.00430

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00314 AC: 4594 AN: 1461890 Hom.: 13 Cov.: 31 AF XY: 0.00304 AC XY: 2208 AN XY: 727248

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00367

Gnomad4 NFE exome AF: 0.00374

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74478

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.00432

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00338 Hom.: 2

Bravo AF: 0.00214

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00279 AC: 339

EpiCase AF: 0.00305

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ABL1: PP2, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

ABL1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D
Eigen	Benign	0.061
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.069
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.048	D;D
Polyphen		0.0050	.;B
Vest4		0.28
MVP		0.45
MPC		0.94
ClinPred		0.069	T
GERP RS		4.9
Varity_R		0.52
gMVP		0.75

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: rs34549764; hg19: chr9-133738340; COSMIC: COSV59334908;