11-119206335-C-A

Variant names:

• chr11-119206335-C-A
• rs1592364458
• ENST00000634586.1:c.-83C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000634586.1(CBL):​c.-83C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 967,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: CBL ENST00000634586.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.699
• Publications: 0 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000634586.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	NM_005188.4	MANE Select	c.-83C>A		upstream_gene	N/A	NP_005179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	ENST00000634586.1	TSL:5	c.-83C>A		5_prime_UTR	Exon 1 of 18	ENSP00000489218.1	A0A0U1RQX8
	CBL	ENST00000634840.1	TSL:5	c.-83C>A		5_prime_UTR	Exon 1 of 15	ENSP00000489324.1	A0A0U1RR39
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.-83C>A		upstream_gene	N/A	ENSP00000264033.3	P22681

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 967858 Hom.: 0 Cov.: 13 AF XY: 0.00000208 AC XY: 1 AN XY: 481352

African (AFR) AF: 0.0000519 AC: 1 AN: 19252

American (AMR) AF: 0.00 AC: 0 AN: 11510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16074

East Asian (EAS) AF: 0.00 AC: 0 AN: 26990

South Asian (SAS) AF: 0.00 AC: 0 AN: 47460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3032

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 773050

Other (OTH) AF: 0.00 AC: 0 AN: 42040

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		0.70
PromoterAI		0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs1592364458; hg19: chr11-119077045;