Genetic Variant ENST00000476370.1:n.4320G>A (chr3-105658671-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The ENST00000476370.1(CBLB):n.4320G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 438,350 control chromosomes in the GnomAD database, including 14,873 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 0.26 ( 5218 hom., cov: 32)

Exomes 𝑓: 0.25 ( 9655 hom. )

Consequence

CBLB
ENST00000476370.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.570

Publications

15 publications found

Variant links:

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)

CBLB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5 link	c.*299G>A		3_prime_UTR_variant	Exon 19 of 19	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8 link	c.*299G>A		3_prime_UTR_variant	Exon 19 of 19	1	NM_170662.5	ENSP00000377598.4		Q13191-1

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39225

AN:

152032

Hom.:

5210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.274

Gnomad AMR

AF:

0.272

Gnomad ASJ

AF:

0.161

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.177

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.271

Gnomad OTH

AF:

0.217

GnomAD4 exome

AF:

0.252

AC:

72234

AN:

286200

Hom.:

9655

Cov.:

AF XY:

0.248

AC XY:

36258

AN XY:

146352

show subpopulations

African (AFR)

AF:

0.231

AC:

2338

AN:

10142

American (AMR)

AF:

0.293

AC:

3302

AN:

11286

Ashkenazi Jewish (ASJ)

AF:

0.154

AC:

1558

AN:

10106

East Asian (EAS)

AF:

0.219

AC:

4831

AN:

22028

South Asian (SAS)

AF:

0.167

AC:

4106

AN:

24548

European-Finnish (FIN)

AF:

0.346

AC:

4918

AN:

14214

Middle Eastern (MID)

AF:

0.155

AC:

208

AN:

1340

European-Non Finnish (NFE)

AF:

0.267

AC:

46518

AN:

174540

Other (OTH)

AF:

0.248

AC:

4455

AN:

17996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2611

5222

7834

10445

13056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.258

AC:

39249

AN:

152150

Hom.:

5218

Cov.:

AF XY:

0.261

AC XY:

19450

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.232

AC:

9651

AN:

41516

American (AMR)

AF:

0.272

AC:

4163

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.161

AC:

558

AN:

3470

East Asian (EAS)

AF:

0.214

AC:

1109

AN:

5176

South Asian (SAS)

AF:

0.178

AC:

857

AN:

4816

European-Finnish (FIN)

AF:

0.353

AC:

3736

AN:

10586

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.271

AC:

18419

AN:

67980

Other (OTH)

AF:

0.216

AC:

457

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1528

3056

4583

6111

7639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.252

Hom.:

14634

Bravo

AF:

0.251

Asia WGS

AF:

0.168

AC:

581

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.8

(source)

DANN

Benign

0.75

PhyloP100

0.57

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over