11-119278199-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_005188.4(CBL):ā€‹c.1129A>Gā€‹(p.Thr377Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

CBL
NM_005188.4 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.95
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a region_of_interest Linker (size 28) in uniprot entity CBL_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005188.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CBLNM_005188.4 linkuse as main transcriptc.1129A>G p.Thr377Ala missense_variant 8/16 ENST00000264033.6 NP_005179.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CBLENST00000264033.6 linkuse as main transcriptc.1129A>G p.Thr377Ala missense_variant 8/161 NM_005188.4 ENSP00000264033.3 P22681

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458364
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
725804
show subpopulations
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:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 25, 2014Variant classified as Uncertain Significance - Favor Benign. The Thr377Ala varia nt in CBL has been previously identified by our laboratory in 2 siblings with a RASopathy, both of whom also carried a likely pathogenic variant in CBL on the o ther allele (in trans configuration). In addition, these individuals' affected p arent carried the likely pathogenic variant, while these individuals' reportedly unaffected parent carried the Thr377Ala variant. It was also absent from large population studies. Computational prediction tools and conservation analysis su ggest that this variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, while the clinical sign ificance of the Thr377Ala variant is uncertain, it is more likely benign since h omozygous or compound heterozygous pathogenic variants in the CBL gene are thoug ht to be incapable with life. However, the current knowledge about this gene and its role in disease is limited and, therefore, at this time it cannot be determ ined if this is a mild variant which plays some role in disease. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 07, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.96
D;.;D;.
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.77
D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Uncertain
2.7
M;.;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-4.7
D;.;.;.
REVEL
Pathogenic
0.82
Sift
Uncertain
0.013
D;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
0.95
P;.;.;.
Vest4
0.96
MutPred
0.41
Loss of ubiquitination at K382 (P = 0.0724);Loss of ubiquitination at K382 (P = 0.0724);Loss of ubiquitination at K382 (P = 0.0724);.;
MVP
0.98
MPC
0.63
ClinPred
0.97
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.75
gMVP
0.55

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.

Other links and lift over

dbSNP: rs727502914; hg19: chr11-119148909; COSMIC: COSV50665784; API