rs560042700

Variant names:

• chr3-105746019-C-A
• rs560042700
• NM_170662.5:c.743G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-105746019-C-A
• chr3-105746019-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170662.5(CBLB):​c.743G>T​(p.Arg248Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R248Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CBLB NM_170662.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89
• Publications: 0 publications found

Genes affected

CBLB (HGNC:1542): (Cbl proto-oncogene B) This gene encodes an E3 ubiquitin-protein ligase which promotes proteosome-mediated protein degradation by transferring ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate. The encoded protein is involved in the regulation of immune response by limiting T-cell receptor, B-cell receptor, and high affinity immunoglobulin epsilon receptor activation. Studies in mouse suggest that this gene is involved in antifungal host defense and that its inhibition leads to increased fungal killing. Manipulation of this gene may be beneficial in implementing immunotherapies for a variety of conditions, including cancer, autoimmune diseases, allergies, and infections. [provided by RefSeq, Sep 2017]

CBLB Gene-Disease associations (from GenCC):

• autoimmune disease, multisystem, infantile-onset, 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5	c.743G>T	p.Arg248Leu	missense_variant	Exon 6 of 19	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8	c.743G>T	p.Arg248Leu	missense_variant	Exon 6 of 19	1	NM_170662.5	ENSP00000377598.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.5	M;M;M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	1.0	N;D;D;D
REVEL	Pathogenic	0.90
Sift	Benign	1.0	T;D;.;D
Sift4G	Uncertain	0.0020	.;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.92, 0.92, 0.93
MutPred		0.69		Gain of catalytic residue at N251 (P = 0.0348);Gain of catalytic residue at N251 (P = 0.0348);Gain of catalytic residue at N251 (P = 0.0348);Gain of catalytic residue at N251 (P = 0.0348);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.85
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs560042700; hg19: chr3-105464863;