rs1047417

Variant names:

• chr11-119301826-A-G
• rs1047417
• NM_005188.4:c.*2045A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-119301826-A-G
• chr11-119301826-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005188.4(CBL):​c.*2045A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 233,018 control chromosomes in the GnomAD database, including 7,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4518 hom., cov: 32)
  • Exomes 𝑓: 0.27 (3107 hom.)
• Consequence: CBL NM_005188.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.340
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-119301826-A-G is Benign according to our data. Variant chr11-119301826-A-G is described in ClinVar as Benign. ClinVar VariationId is 302818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4	c.*2045A>G		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.*2045A>G		3_prime_UTR_variant	Exon 16 of 16	1	NM_005188.4	ENSP00000264033.3

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36286 AN: 151964 Hom.: 4512 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.242

GnomAD4 exome AF: 0.274 AC: 22155 AN: 80936 Hom.: 3107 Cov.: 0 AF XY: 0.273 AC XY: 10148 AN XY: 37198

African (AFR) AF: 0.221 AC: 860 AN: 3894

American (AMR) AF: 0.206 AC: 514 AN: 2500

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1726 AN: 5122

East Asian (EAS) AF: 0.358 AC: 4082 AN: 11404

South Asian (SAS) AF: 0.154 AC: 108 AN: 702

European-Finnish (FIN) AF: 0.267 AC: 16 AN: 60

Middle Eastern (MID) AF: 0.278 AC: 137 AN: 492

European-Non Finnish (NFE) AF: 0.259 AC: 12955 AN: 49998

Other (OTH) AF: 0.260 AC: 1757 AN: 6764

GnomAD4 genome AF: 0.239 AC: 36307 AN: 152082 Hom.: 4518 Cov.: 32 AF XY: 0.238 AC XY: 17716 AN XY: 74334

African (AFR) AF: 0.209 AC: 8648 AN: 41476

American (AMR) AF: 0.200 AC: 3050 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1155 AN: 3470

East Asian (EAS) AF: 0.342 AC: 1769 AN: 5174

South Asian (SAS) AF: 0.165 AC: 797 AN: 4828

European-Finnish (FIN) AF: 0.258 AC: 2726 AN: 10558

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17371 AN: 67980

Other (OTH) AF: 0.244 AC: 514 AN: 2106

Alfa AF: 0.252 Hom.: 21647

Bravo AF: 0.236

Asia WGS AF: 0.267 AC: 933 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CBL-related disorder Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.53
DANN	Benign	0.23
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1047417; hg19: chr11-119172536;