rs994847890

Variant names:

• chr11-119206322-G-GCGA
• rs994847890
• ENST00000634586.1:c.-95_-94insGAC

Your query was ambiguous. Multiple possible variants found:

• chr11-119206322-G-GCGA
• chr11-119206322-G-GCGGCGA
• chr11-119206322-G-GCGGCGGCGA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000634586.1(CBL):​c.-95_-94insGAC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000358 in 1,034,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: CBL ENST00000634586.1 5_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.421
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000198 (30/151828) while in subpopulation AFR AF = 0.000725 (30/41368). AF 95% confidence interval is 0.000521. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 30 AD gene.

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.-96_-95insCGA		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.-95_-94insGAC		5_prime_UTR	Exon 1 of 18	ENSP00000489218.1	A0A0U1RQX8
	CBL	ENST00000634840.1	TSL:5	c.-95_-94insGAC		5_prime_UTR	Exon 1 of 15	ENSP00000489324.1	A0A0U1RR39
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.-96_-95insCGA		upstream_gene	N/A	ENSP00000264033.3	P22681

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000793 AC: 7 AN: 882558 Hom.: 0 Cov.: 12 AF XY: 0.00000455 AC XY: 2 AN XY: 439490

African (AFR) AF: 0.000174 AC: 3 AN: 17272

American (AMR) AF: 0.000104 AC: 1 AN: 9632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14632

East Asian (EAS) AF: 0.00 AC: 0 AN: 26232

South Asian (SAS) AF: 0.00 AC: 0 AN: 37470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 708952

Other (OTH) AF: 0.0000775 AC: 3 AN: 38730

GnomAD4 genome AF: 0.000198 AC: 30 AN: 151828 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74150

African (AFR) AF: 0.000725 AC: 30 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67840

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	CBL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.42

Splicing

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

Other links and lift over

dbSNP: rs994847890; hg19: chr11-119077032;