rs61741003

Positions:

chr9-130854112-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_005157.6(ABL1):c.128G>A(p.Ser43Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,614,142 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

ABL1
NM_005157.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 2.85

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 -19 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=0.00839448).

BP6

Variant 9-130854112-G-A is Benign according to our data. Variant chr9-130854112-G-A is described in ClinVar as [Benign]. Clinvar id is 133448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130854112-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00167 (255/152260) while in subpopulation AFR AF= 0.00554 (230/41548). AF 95% confidence interval is 0.00495. There are 1 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 255 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABL1	NM_005157.6 linkuse as main transcript	c.128G>A	p.Ser43Asn	missense_variant	2/11	ENST00000318560.6	NP_005148.2
ABL1	NM_007313.3 linkuse as main transcript	c.185G>A	p.Ser62Asn	missense_variant	2/11		NP_009297.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000318560.6 linkuse as main transcript	c.128G>A	p.Ser43Asn	missense_variant	2/11	1	NM_005157.6	ENSP00000323315		P00519-1
ABL1	ENST00000372348.9 linkuse as main transcript	c.185G>A	p.Ser62Asn	missense_variant	2/11	1		ENSP00000361423	P1	P00519-2
ABL1	ENST00000393293.4 linkuse as main transcript	c.182G>A	p.Ser61Asn	missense_variant	2/2	5		ENSP00000376971

Frequencies

GnomAD3 genomes

AF:

0.00167

AC:

254

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00553

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000481

AC:

121

AN:

251426

Hom.:

AF XY:

0.000390

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00498

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000254

AC:

372

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000248

AC XY:

180

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00591

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000881

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.00167

AC:

255

AN:

152260

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

118

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00554

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000343

Hom.:

Bravo

AF:

0.00184

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ABL1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 06, 2020

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

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

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.093

.;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

0.074

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

.;.;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.42

N;D;N

REVEL

Benign

0.073

Sift

Benign

0.64

T;D;T

Sift4G

Benign

0.67

T;D;T

Polyphen

0.012

.;.;B

Vest4

0.15

MVP

0.23

MPC

0.23

ClinPred

0.014

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.076

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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