11-119278182-A-C

Position:

• chr11-119278182-A-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_005188.4(CBL):​c.1112A>C​(p.Tyr371Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y371H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.95

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a region_of_interest Linker (size 28) in uniprot entity CBL_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005188.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-119278181-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 11-119278182-A-C is Pathogenic according to our data. Variant chr11-119278182-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBL	NM_005188.4	c.1112A>C	p.Tyr371Ser	missense_variant	8/16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.1112A>C	p.Tyr371Ser	missense_variant	8/16	1	NM_005188.4	ENSP00000264033	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450284 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 26, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2024

Published functional studies demonstrate the variant results in abnormal protein function (PMID: 19620960); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27609087, 33627783, 20501843, 31216405, 22131879, 33144682, 19620960, 20619386, 22315494) -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr371 amino acid residue in CBL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20543203, 20694012, 25283271, 25952305, 28414188). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CBL function (PMID: 19620960, 27609087). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBL protein function. ClinVar contains an entry for this variant (Variation ID: 548022). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 371 of the CBL protein (p.Tyr371Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.97	D;.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.5	D;.;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.73		Gain of disorder (P = 0.0098);Gain of disorder (P = 0.0098);Gain of disorder (P = 0.0098);.;
MVP		0.99
MPC		0.93
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.78

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: rs387906666; hg19: chr11-119148892; COSMIC: COSV50637098;