rs3833768

Variant names:

• chr11-119300340-T-TC
• rs3833768
• NM_005188.4:c.*559_*560insC

Your query was ambiguous. Multiple possible variants found:

• chr11-119300340-T-TC
• chr11-119300340-T-TCA
• chr11-119300340-T-TCAA
• chr11-119300340-T-TCAATA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005188.4(CBL):​c.*559_*560insC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 410,686 control chromosomes in the GnomAD database, including 14,251 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4644 hom., cov: 32)
  • Exomes 𝑓: 0.27 (9607 hom.)
• Consequence: CBL NM_005188.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00700

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 11-119300340-T-TC is Benign according to our data. Variant chr11-119300340-T-TC is described in ClinVar as [Likely_benign]. Clinvar id is 210588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36901 AN: 151814 Hom.: 4637 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.246

GnomAD4 exome AF: 0.267 AC: 69081 AN: 258754 Hom.: 9607 Cov.: 0 AF XY: 0.266 AC XY: 34920 AN XY: 131480

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.341

Gnomad4 EAS exome AF: 0.386

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.243 AC: 36925 AN: 151932 Hom.: 4644 Cov.: 32 AF XY: 0.243 AC XY: 18048 AN XY: 74240

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.248

Alfa AF: 0.0692 Hom.: 137

Asia WGS AF: 0.277 AC: 966 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Jan 20, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs3833768; hg19: chr11-119171050; COSMIC: COSV50631555;