11-119278165-G-C

Variant names:

• chr11-119278165-G-C
• rs397517076
• NM_005188.4:c.1096-1G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_005188.4(CBL):​c.1096-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBL NM_005188.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.60

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.048511576 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of -43, new splice context is: gttaacatttataattgcAGtta. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-119278165-G-C is Pathogenic according to our data. Variant chr11-119278165-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.1096-1G>C		splice_acceptor_variant, intron_variant	Intron 7 of 15	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.1096-1G>C		splice_acceptor_variant, intron_variant	Intron 7 of 15	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438556 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 716954

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

Alfa AF: 0.0000301 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder Pathogenic:1

Aug 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jan 26, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome-like disorder with juvenile myelomonocytic leukemia Pathogenic:1

May 18, 2020

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CBL c.1096-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in a heterozygous state in one child with juvenile myelomonocytic leukemia who also presented with café-au-lait spots, juvenile xanthogranuloma, cryptorchidism, poor growth, developmental delay, and supraventricular tachycardia (Niemeyer et al. 2010). In addition, evaluation of non-germline cells in this child and two additional individuals showed the c.1096-1G>C variant present in a either a homozygous or heterozygous state (Loh et al. 2009; Niemeyer et al. 2010; Strullu et al. 2013). The c.1096-1G>C variant is located in intron 7. RT-PCR showed the presence of in-frame protein products lacking exon 8, which encompasses the functionally important RING finger domain (Abbas et al. 2008; Niemeyer et al. 2010). Additional splice site variants at the same genomic position with different base changes have also been described in individuals with RASopathy or Noonan-like phenotypes (Strullu et al. 2013; Bulow et al. 2015; Seaby et al. 2017). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage. Based on the collective evidence, the c.1096-1G>C variant is classified as pathogenic for Noonan syndrome-like disorder with juvenile myelomonocytic leukemia. -

Noonan syndrome Pathogenic:1

Dec 06, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 1096-1G>C variant in CBL has been reported in one individual with clinical f eatures of Noonan syndrome and juvenile myelomonocytic leukemia (JMML; Loh 2009, Niemeyer 2010). This variant was reported to be homozygous in a blood sample an d heterozygous in the germline. Studies have shown that the 1096-1G>A variant i mpacts splicing (Niemeyer 2010). In addition, this variant was not identified in either parent of this individual and therefore likely occurred de novo, assumin g that non-medical explanations including alternate paternity or undisclosed ado ption have been ruled out. This finding supports that this variant is disease ca using and responsible for Noonan-like syndrome and juvenile myelomonocytic leuke mia in this individual. In summary, this variant meets our criteria to be classi fied as pathogenic (http://pcpgm.partners.org/LMM). -

RASopathy Pathogenic:1

Dec 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 45196). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 25952305). Disruption of this splice site has been observed in individual(s) with CBL-related conditions (PMID: 25358541; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 7 of the CBL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -

not provided Other:1

-

MutSpliceDB: a database of splice sites variants effects on splicing, NIH

Significance: not provided

Review Status: no classification provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397517076; hg19: chr11-119148875; COSMIC: COSV50631547;