rs2229067

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005157.6(ABL1):c.2915C>T(p.Ser972Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,586 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S972P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.028 ( 87 hom., cov: 33)

Exomes 𝑓: 0.018 ( 350 hom. )

Consequence

ABL1
NM_005157.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 0.616

Publications

22 publications found

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]

ABL1 Gene-Disease associations (from GenCC):

congenital heart defects and skeletal malformations syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
connective tissue disorder
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
bone development disease
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ABL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021662712).

BP6

Variant 9-130885205-C-T is Benign according to our data. Variant chr9-130885205-C-T is described in ClinVar as Benign. ClinVar VariationId is 133443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0279 (4250/152332) while in subpopulation AFR AF = 0.0396 (1647/41578). AF 95% confidence interval is 0.038. There are 87 homozygotes in GnomAd4. There are 2164 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 87 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABL1	NM_005157.6 link	c.2915C>T	p.Ser972Leu	missense_variant	Exon 11 of 11	ENST00000318560.6	NP_005148.2	P00519-1A0A024R8E2Q59FK4
ABL1	NM_007313.3 link	c.2972C>T	p.Ser991Leu	missense_variant	Exon 11 of 11		NP_009297.2	P00519-2Q59FK4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000318560.6 link	c.2915C>T	p.Ser972Leu	missense_variant	Exon 11 of 11	1	NM_005157.6	ENSP00000323315.5		P00519-1
ABL1	ENST00000372348.9 link	c.2972C>T	p.Ser991Leu	missense_variant	Exon 11 of 11	1		ENSP00000361423.2		P00519-2

Frequencies

GnomAD3 genomes

AF:

0.0279

AC:

4247

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0397

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.0338

Gnomad ASJ

AF:

0.0565

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0376

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.0210

AC:

5260

AN:

250232

AF XY:

0.0203

show subpopulations

Gnomad AFR exome

AF:

0.0405

Gnomad AMR exome

AF:

0.0223

Gnomad ASJ exome

AF:

0.0559

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0410

Gnomad NFE exome

AF:

0.0195

Gnomad OTH exome

AF:

0.0254

GnomAD4 exome

AF:

0.0175

AC:

25636

AN:

1461254

Hom.:

350

Cov.:

AF XY:

0.0173

AC XY:

12553

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.0413

AC:

1382

AN:

33472

American (AMR)

AF:

0.0227

AC:

1017

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0535

AC:

1399

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00124

AC:

107

AN:

86252

European-Finnish (FIN)

AF:

0.0389

AC:

2056

AN:

52850

Middle Eastern (MID)

AF:

0.0407

AC:

235

AN:

5768

European-Non Finnish (NFE)

AF:

0.0162

AC:

17990

AN:

1111970

Other (OTH)

AF:

0.0240

AC:

1449

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1821

3643

5464

7286

9107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

680

1360

2040

2720

3400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0279

AC:

4250

AN:

152332

Hom.:

Cov.:

AF XY:

0.0291

AC XY:

2164

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0396

AC:

1647

AN:

41578

American (AMR)

AF:

0.0338

AC:

518

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0565

AC:

196

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0376

AC:

399

AN:

10624

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0186

AC:

1263

AN:

68022

Other (OTH)

AF:

0.0332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

221

442

662

883

1104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0212

Hom.:

197

Bravo

AF:

0.0283

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.0431

AC:

190

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0197

AC:

2385

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0194

EpiControl

AF:

0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

.;N

PhyloP100

0.62

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.021

Sift

Benign

0.20

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0010

.;B

Vest4

0.033

MPC

0.18

ClinPred

0.012

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.020

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over