rs61746126

Positions:

chr9-130884299-A-G

Variant summary

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

The NM_005157.6(ABL1):c.2009A>G(p.Asn670Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000419 in 1,609,178 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00042 ( 2 hom. )

Consequence

ABL1
NM_005157.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.28

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=0.056831628).

BP6

Variant 9-130884299-A-G is Benign according to our data. Variant chr9-130884299-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 133434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000423 (616/1456892) while in subpopulation SAS AF= 0.000745 (64/85910). AF 95% confidence interval is 0.000598. There are 2 homozygotes in gnomad4_exome. There are 332 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABL1	NM_005157.6 linkuse as main transcript	c.2009A>G	p.Asn670Ser	missense_variant	11/11	ENST00000318560.6	NP_005148.2	P00519-1A0A024R8E2Q59FK4
ABL1	NM_007313.3 linkuse as main transcript	c.2066A>G	p.Asn689Ser	missense_variant	11/11		NP_009297.2	P00519-2Q59FK4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABL1	ENST00000318560.6 linkuse as main transcript	c.2009A>G	p.Asn670Ser	missense_variant	11/11	1	NM_005157.6	ENSP00000323315.5		P00519-1
ABL1	ENST00000372348.9 linkuse as main transcript	c.2066A>G	p.Asn689Ser	missense_variant	11/11	1		ENSP00000361423.2		P00519-2

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000369

AC:

AN:

244212

Hom.:

AF XY:

0.000399

AC XY:

AN XY:

132960

show subpopulations

Gnomad AFR exome

AF:

0.000262

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.000553

Gnomad SAS exome

AF:

0.000530

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000410

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.000423

AC:

616

AN:

1456892

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

332

AN XY:

724462

show subpopulations

Gnomad4 AFR exome

AF:

0.000241

Gnomad4 AMR exome

AF:

0.000362

Gnomad4 ASJ exome

AF:

0.0000771

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.000745

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.000434

Gnomad4 OTH exome

AF:

0.000499

GnomAD4 genome

AF:

0.000381

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000407

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.000355

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 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

0.075

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T

Eigen

Benign

-0.0050

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.0062

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.86

N;N

REVEL

Benign

0.11

Sift

Benign

0.092

T;T

Sift4G

Benign

0.74

T;T

Polyphen

0.40

.;B

Vest4

0.33

MVP

0.38

MPC

0.17

ClinPred

0.021

GERP RS

5.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.084

gMVP

0.20

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