11-119278676-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005188.4(CBL):​c.1394A>T​(p.Asp465Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CBL
NM_005188.4 missense

Scores

3
12
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.60
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CBLNM_005188.4 linkc.1394A>T p.Asp465Val missense_variant 9/16 ENST00000264033.6 NP_005179.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CBLENST00000264033.6 linkc.1394A>T p.Asp465Val missense_variant 9/161 NM_005188.4 ENSP00000264033.3 P22681

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152066
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251298
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135798
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461864
Hom.:
0
Cov.:
33
AF XY:
0.00000963
AC XY:
7
AN XY:
727238
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:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152066
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 28, 2024- -
CBL-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 08, 2023The CBL c.1394A>T variant is predicted to result in the amino acid substitution p.Asp465Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-119149386-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 05, 2024The p.D465V variant (also known as c.1394A>T), located in coding exon 9 of the CBL gene, results from an A to T substitution at nucleotide position 1394. The aspartic acid at codon 465 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 01, 2024This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 465 of the CBL protein (p.Asp465Val). This variant is present in population databases (rs770644035, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 573622). 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 not expected to disrupt CBL protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.74
D;.;T;.
Eigen
Uncertain
0.62
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Benign
0.061
D
MetaRNN
Uncertain
0.52
D;D;D;D
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
2.0
M;.;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-2.3
N;.;.;.
REVEL
Uncertain
0.54
Sift
Uncertain
0.0030
D;.;.;.
Sift4G
Uncertain
0.020
D;D;T;.
Polyphen
0.96
D;.;.;.
Vest4
0.78
MutPred
0.36
Gain of catalytic residue at D465 (P = 0.0078);Gain of catalytic residue at D465 (P = 0.0078);Gain of catalytic residue at D465 (P = 0.0078);.;
MVP
0.94
MPC
0.51
ClinPred
0.44
T
GERP RS
6.0
Varity_R
0.39
gMVP
0.57

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: rs770644035; hg19: chr11-119149386; API