11-119300340-T-TCAA

Variant names:

• chr11-119300340-T-TCAA
• rs3833768
• NM_005188.4:c.*559_*560insCAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005188.4(CBL):​c.*559_*560insCAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBL NM_005188.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.00700
• Publications: 3 publications found

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]

CBL Gene-Disease associations (from GenCC):

• CBL-related disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Genomics England PanelApp
• juvenile myelomonocytic leukemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.*559_*560insCAA		3_prime_UTR_variant	Exon 16 of 16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.*559_*560insCAA		3_prime_UTR_variant	Exon 16 of 16	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 258804 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131506

African (AFR) AF: 0.00 AC: 0 AN: 7288

American (AMR) AF: 0.00 AC: 0 AN: 10108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9352

East Asian (EAS) AF: 0.00 AC: 0 AN: 23560

South Asian (SAS) AF: 0.00 AC: 0 AN: 4262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1318

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 164702

Other (OTH) AF: 0.00 AC: 0 AN: 16828

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 137

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan-like syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0070

Splicing

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

Other links and lift over

dbSNP: rs3833768; hg19: chr11-119171050;