3-105720058-T-C

Position:

• chr3-105720058-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_170662.5(CBLB):​c.1396A>G​(p.Asn466Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,612 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: CBLB NM_170662.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003571868).
• BP6: Variant 3-105720058-T-C is Benign according to our data. Variant chr3-105720058-T-C is described in ClinVar as [Benign]. Clinvar id is 133818.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-105720058-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00164 (250/152274) while in subpopulation EAS AF= 0.0453 (235/5186). AF 95% confidence interval is 0.0406. There are 3 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBLB	NM_170662.5	c.1396A>G	p.Asn466Asp	missense_variant	10/19	ENST00000394030.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLB	ENST00000394030.8	c.1396A>G	p.Asn466Asp	missense_variant	10/19	1	NM_170662.5	P1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152156 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0452

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00405 AC: 1017 AN: 251104 Hom.: 23 AF XY: 0.00367 AC XY: 498 AN XY: 135742

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0539

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00107 AC: 1559 AN: 1461338 Hom.: 27 Cov.: 32 AF XY: 0.00102 AC XY: 742 AN XY: 727020

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0350

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152274 Hom.: 3 Cov.: 31 AF XY: 0.00177 AC XY: 132 AN XY: 74458

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0453

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00229 Hom.: 8

Bravo AF: 0.00220

ExAC AF: 0.00400 AC: 486

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

CBLB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	.;D;D;D
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.90	L;L;L;L
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.31	.;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.043	.;D;.;T
Sift4G	Benign	0.66	.;T;T;T
Polyphen		0.061	B;B;B;.
Vest4		0.27, 0.27, 0.27
MVP		0.80
MPC		0.60
ClinPred		0.017	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066

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: rs61758360; hg19: chr3-105438902; COSMIC: COSV51423525;