rs62638716

Positions:

chr9-130878562-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.1418G>A(p.Arg473Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000506 in 1,614,130 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

ABL1
NM_005157.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.16

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=0.01002726).

BP6

Variant 9-130878562-G-A is Benign according to our data. Variant chr9-130878562-G-A is described in ClinVar as [Benign]. Clinvar id is 133453.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 = 0.0028 (427/152320) while in subpopulation AFR AF= 0.00991 (412/41578). AF 95% confidence interval is 0.00912. There are 1 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 427 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABL1	NM_005157.6 linkuse as main transcript	c.1418G>A	p.Arg473Gln	missense_variant	8/11	ENST00000318560.6	NP_005148.2	P00519-1A0A024R8E2Q59FK4
ABL1	NM_007313.3 linkuse as main transcript	c.1475G>A	p.Arg492Gln	missense_variant	8/11		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.1418G>A	p.Arg473Gln	missense_variant	8/11	1	NM_005157.6	ENSP00000323315.5		P00519-1
ABL1	ENST00000372348.9 linkuse as main transcript	c.1475G>A	p.Arg492Gln	missense_variant	8/11	1		ENSP00000361423.2		P00519-2

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00996

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000633

AC:

159

AN:

251358

Hom.:

AF XY:

0.000442

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00867

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000267

AC:

390

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00914

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00280

AC:

427

AN:

152320

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00991

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000445

Hom.:

Bravo

AF:

0.00302

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000840

AC:

102

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

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 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

0.087

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;D

Eigen

Benign

-0.057

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.64

.;N

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.35

Sift

Benign

0.042

D;D

Sift4G

Benign

0.086

T;T

Polyphen

0.55

.;P

Vest4

0.34

MVP

0.83

MPC

2.5

ClinPred

0.062

GERP RS

3.9

Varity_R

0.72

gMVP

0.76

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