9-130885205-C-T

Position:

chr9-130885205-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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, single submitter B:1O:1

Conservation

PhyloP100: 0.616

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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=0.0021662712).

BP6

Variant 9-130885205-C-T is Benign according to our data. Variant chr9-130885205-C-T is described in ClinVar as [Benign]. Clinvar id is 133443.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-130885205-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4250 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABL1	NM_005157.6 linkuse as main transcript	c.2915C>T	p.Ser972Leu	missense_variant	11/11	ENST00000318560.6
ABL1	NM_007313.3 linkuse as main transcript	c.2972C>T	p.Ser991Leu	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABL1	ENST00000318560.6 linkuse as main transcript	c.2915C>T	p.Ser972Leu	missense_variant	11/11	1	NM_005157.6		P00519-1
ABL1	ENST00000372348.9 linkuse as main transcript	c.2972C>T	p.Ser991Leu	missense_variant	11/11	1		P1	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

GnomAD3 exomes

AF:

0.0210

AC:

5260

AN:

250232

Hom.:

AF XY:

0.0203

AC XY:

2756

AN XY:

135534

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 SAS exome

AF:

0.00114

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

Gnomad4 AFR exome

AF:

0.0413

Gnomad4 AMR exome

AF:

0.0227

Gnomad4 ASJ exome

AF:

0.0535

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00124

Gnomad4 FIN exome

AF:

0.0389

Gnomad4 NFE exome

AF:

0.0162

Gnomad4 OTH exome

AF:

0.0240

GnomAD4 genome

AF:

0.0279

AC:

4250

AN:

152332

Hom.:

Cov.:

AF XY:

0.0291

AC XY:

2164

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0396

Gnomad4 AMR

AF:

0.0338

Gnomad4 ASJ

AF:

0.0565

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0376

Gnomad4 NFE

AF:

0.0186

Gnomad4 OTH

AF:

0.0332

Alfa

AF:

0.0214

Hom.:

108

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:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

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

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

MutationTaster

Benign

1.0

N;N

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over