NM_005188.4:c.*560_*561insAT

Variant names:

• chr11-119300341-A-AAT
• rs56722042
• NM_005188.4:c.*560_*561insAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005188.4(CBL):​c.*560_*561insAT 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 409,830 control chromosomes in the GnomAD database, including 14,217 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4646 hom., cov: 32)
  • Exomes 𝑓: 0.27 (9571 hom.)
• Consequence: CBL NM_005188.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.315
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 11-119300341-A-AAT is Benign according to our data. Variant chr11-119300341-A-AAT is described in CliVar as Likely_benign. Clinvar id is 210589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119300341-A-AAT is described in CliVar as Likely_benign. Clinvar id is 210589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119300341-A-AAT is described in CliVar as Likely_benign. Clinvar id is 210589.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.*560_*561insAT		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.*560_*561insAT		3_prime_UTR_variant	Exon 16 of 16	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36905 AN: 151688 Hom.: 4639 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: 0.386

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.267 AC: 68901 AN: 258024 Hom.: 9571 Cov.: 0 AF XY: 0.266 AC XY: 34851 AN XY: 131146

African (AFR) AF: 0.211 AC: 1531 AN: 7268

American (AMR) AF: 0.183 AC: 1834 AN: 9998

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 3181 AN: 9328

East Asian (EAS) AF: 0.386 AC: 9049 AN: 23470

South Asian (SAS) AF: 0.151 AC: 633 AN: 4180

European-Finnish (FIN) AF: 0.252 AC: 5382 AN: 21356

Middle Eastern (MID) AF: 0.273 AC: 359 AN: 1314

European-Non Finnish (NFE) AF: 0.259 AC: 42525 AN: 164306

Other (OTH) AF: 0.262 AC: 4407 AN: 16804

GnomAD4 genome AF: 0.243 AC: 36929 AN: 151806 Hom.: 4646 Cov.: 32 AF XY: 0.243 AC XY: 18050 AN XY: 74164

African (AFR) AF: 0.209 AC: 8645 AN: 41406

American (AMR) AF: 0.200 AC: 3059 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1156 AN: 3470

East Asian (EAS) AF: 0.386 AC: 1983 AN: 5136

South Asian (SAS) AF: 0.166 AC: 801 AN: 4816

European-Finnish (FIN) AF: 0.272 AC: 2857 AN: 10514

Middle Eastern (MID) AF: 0.228 AC: 66 AN: 290

European-Non Finnish (NFE) AF: 0.260 AC: 17634 AN: 67876

Other (OTH) AF: 0.248 AC: 524 AN: 2116

Alfa AF: 0.253 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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs56722042; hg19: chr11-119171051; COSMIC: COSV50631559;