3-105867870-T-C

Variant names:

• chr3-105867870-T-C
• rs9657904
• NM_170662.5:c.-14-279A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_170662.5(CBLB):​c.-14-279A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 146,616 control chromosomes in the GnomAD database, including 4,538 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4538 hom., cov: 30)
• Consequence: CBLB NM_170662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.593
• Publications: 44 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5	c.-14-279A>G		intron_variant	Intron 1 of 18	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8	c.-14-279A>G		intron_variant	Intron 1 of 18	1	NM_170662.5	ENSP00000377598.4

Frequencies

GnomAD3 genomes AF: 0.243 AC: 35677 AN: 146528 Hom.: 4526 Cov.: 30

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.132

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.222

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.244 AC: 35718 AN: 146616 Hom.: 4538 Cov.: 30 AF XY: 0.248 AC XY: 17637 AN XY: 71138

African (AFR) AF: 0.297 AC: 11957 AN: 40224

American (AMR) AF: 0.245 AC: 3594 AN: 14658

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 542 AN: 3320

East Asian (EAS) AF: 0.479 AC: 2410 AN: 5028

South Asian (SAS) AF: 0.261 AC: 1145 AN: 4382

European-Finnish (FIN) AF: 0.228 AC: 2118 AN: 9290

Middle Eastern (MID) AF: 0.136 AC: 38 AN: 280

European-Non Finnish (NFE) AF: 0.199 AC: 13236 AN: 66490

Other (OTH) AF: 0.223 AC: 454 AN: 2038

Alfa AF: 0.219 Hom.: 12293

Bravo AF: 0.247

Asia WGS AF: 0.336 AC: 1143 AN: 3406

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.89
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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: rs9657904; hg19: chr3-105586714;