rs1060500676

chr11-119278235-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 PP3_Moderate PP5

The NM_005188.4(CBL):c.1165A>G(p.Lys389Glu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K389T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.95

Genes affected

CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_005188.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-119278236-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 11-119278235-A-G is Pathogenic according to our data. Variant chr11-119278235-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405365.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBL	NM_005188.4	c.1165A>G	p.Lys389Glu	missense_variant	8/16	ENST00000264033.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBL	ENST00000264033.6	c.1165A>G	p.Lys389Glu	missense_variant	8/16	1	NM_005188.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460302 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726616

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CBL-related disorder Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 07, 2021	The CBL c.1165A>G (p.Lys389Glu) missense change replaces lysine with glutamic acid at codon 389 of the CBL gene and is absent in population databases including gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). The lysine residue is located in the RING finger domain which is a known mutational hotspot in myeloid malignancies and the location of germline pathogenic variants causing Noonan syndrome-like disorder (PM1; PMID: 20619386). This variant has been identified in an individual with juvenile myelomonocytic leukemia (JMML) in which the tumor exhibited a second pathogenic variant in the CBL gene (PS4_supporting, PP4; internal data). This is consistent with the mechanism of leukemogenesis in individuals with JMML and pathogenic germline variants in CBL (PMID: 20694012, 33375775). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). There is a different pathogenic variant (p.Lys389Thr) previously reported at this codon (ClinVar Accession: SCV001826631.1, SCV001445234.1). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied: PS4_supporting, PM1, PM2_supporting, PP3, PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 12, 2022	- -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 18, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBL protein function. ClinVar contains an entry for this variant (Variation ID: 405365). This variant has not been reported in the literature in individuals affected with CBL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 389 of the CBL protein (p.Lys389Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.90
MutPred		0.71		Loss of ubiquitination at K389 (P = 0.0155);Loss of ubiquitination at K389 (P = 0.0155);Loss of ubiquitination at K389 (P = 0.0155);.;
MVP		0.99
MPC		0.92
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.72

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

Other links and lift over

dbSNP: rs1060500676; hg19: chr11-119148945;