11-119278199-A-G

Variant names:

• chr11-119278199-A-G
• rs727502914
• NM_005188.4:c.1129A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005188.4(CBL):​c.1129A>G​(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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 13) 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 rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.1129A>G	p.Thr377Ala	missense_variant	Exon 8 of 16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.1129A>G	p.Thr377Ala	missense_variant	Exon 8 of 16	1	NM_005188.4	ENSP00000264033.3

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

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

Submissions by phenotype

not specified Uncertain:1

Sep 25, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant 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

Sep 07, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Other links and lift over

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