NM_005157.6:c.2915C>T

Variant names:

• chr9-130885205-C-T
• rs2229067
• NM_005157.6:c.2915C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.616
• Publications: 22 publications found

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: G2P, Labcorp Genetics (formerly Invitae)
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• bone development disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005157.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABL1	NM_005157.6	MANE Select	c.2915C>T	p.Ser972Leu	missense	Exon 11 of 11	NP_005148.2	P00519-1
	ABL1	NM_007313.3		c.2972C>T	p.Ser991Leu	missense	Exon 11 of 11	NP_009297.2	P00519-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABL1	ENST00000318560.6	TSL:1 MANE Select	c.2915C>T	p.Ser972Leu	missense	Exon 11 of 11	ENSP00000323315.5	P00519-1
	ABL1	ENST00000372348.9	TSL:1	c.2972C>T	p.Ser991Leu	missense	Exon 11 of 11	ENSP00000361423.2	P00519-2
	ABL1	ENST00000929254.1		c.2912C>T	p.Ser971Leu	missense	Exon 11 of 11	ENSP00000599313.1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4247 AN: 152214 Hom.: 87 Cov.: 33

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

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.: 32 AF XY: 0.0173 AC XY: 12553 AN XY: 726944

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: 1 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

GnomAD4 genome AF: 0.0279 AC: 4250 AN: 152332 Hom.: 87 Cov.: 33 AF XY: 0.0291 AC XY: 2164 AN XY: 74492

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: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0376 AC: 399 AN: 10624

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1263 AN: 68022

Other (OTH) AF: 0.0332 AC: 70 AN: 2110

Alfa AF: 0.0212 Hom.: 197

Bravo AF: 0.0283

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.0431 AC: 190

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0197 AC: 2385

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0194

EpiControl AF: 0.0224

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.74	T
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	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.62
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.021
Sift	Benign	0.20	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.033
MPC		0.18
ClinPred		0.012	T
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)

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

Other links and lift over

dbSNP: rs2229067; hg19: chr9-133760592;