chr11-119206322-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000634586.1(CBL):​c.-96G>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 0.00192 in 1,034,480 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 24 hom., cov: 32)
Exomes 𝑓: 0.00081 ( 15 hom. )

Consequence

CBL
ENST00000634586.1 5_prime_UTR

Scores

1
1

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.663
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
Variant 11-119206322-G-A is Benign according to our data. Variant chr11-119206322-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 302772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00838 (1273/151932) while in subpopulation AFR AF= 0.0293 (1215/41482). AF 95% confidence interval is 0.0279. There are 24 homozygotes in gnomad4. There are 603 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1273 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CBLNM_005188.4 linkuse as main transcript upstream_gene_variant ENST00000264033.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CBLENST00000634586.1 linkuse as main transcriptc.-96G>A 5_prime_UTR_variant 1/185
CBLENST00000634840.1 linkuse as main transcriptc.-96G>A 5_prime_UTR_variant 1/155 A2
CBLENST00000264033.6 linkuse as main transcript upstream_gene_variant 1 NM_005188.4 P2
CBLENST00000700472.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD3 genomes
AF:
0.00835
AC:
1267
AN:
151824
Hom.:
23
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0292
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00177
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000379
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.000251
Gnomad OTH
AF:
0.00384
GnomAD4 exome
AF:
0.000809
AC:
714
AN:
882548
Hom.:
15
Cov.:
12
AF XY:
0.000687
AC XY:
302
AN XY:
439484
show subpopulations
Gnomad4 AFR exome
AF:
0.0294
Gnomad4 AMR exome
AF:
0.00156
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000267
Gnomad4 FIN exome
AF:
0.000409
Gnomad4 NFE exome
AF:
0.000154
Gnomad4 OTH exome
AF:
0.00183
GnomAD4 genome
AF:
0.00838
AC:
1273
AN:
151932
Hom.:
24
Cov.:
32
AF XY:
0.00812
AC XY:
603
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.0293
Gnomad4 AMR
AF:
0.00177
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000379
Gnomad4 NFE
AF:
0.000251
Gnomad4 OTH
AF:
0.00380
Alfa
AF:
0.00707
Hom.:
2
Bravo
AF:
0.00912
Asia WGS
AF:
0.00145
AC:
5
AN:
3450

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxAug 15, 2019- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
CBL-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.56
CADD
Benign
14
DANN
Uncertain
0.98
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.1

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs548262208; hg19: chr11-119077032; API