rs2240017

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_013351.2(TBX21):c.99C>G(p.His33Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 1,487,136 control chromosomes in the GnomAD database, including 1,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.030 ( 157 hom., cov: 32)

Exomes 𝑓: 0.031 ( 911 hom. )

Consequence

TBX21
NM_013351.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.991

Publications

46 publications found

Variant links:

Genes affected

TBX21 (HGNC:11599): (T-box transcription factor 21) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells. [provided by RefSeq, Jul 2008]

TBX21 Gene-Disease associations (from GenCC):

immunodeficiency 88
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TBX21 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011099577).

BP6

Variant 17-47733553-C-G is Benign according to our data. Variant chr17-47733553-C-G is described in ClinVar as Benign. ClinVar VariationId is 2688320.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX21	NM_013351.2 link	c.99C>G	p.His33Gln	missense_variant	Exon 1 of 6	ENST00000177694.2	NP_037483.1	Q9UL17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX21	ENST00000177694.2 link	c.99C>G	p.His33Gln	missense_variant	Exon 1 of 6	1	NM_013351.2	ENSP00000177694.1		Q9UL17
TBX21	ENST00000581328.1 link	n.129C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0301

AC:

4577

AN:

152020

Hom.:

156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0789

Gnomad ASJ

AF:

0.0703

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.0534

Gnomad FIN

AF:

0.00387

Gnomad MID

AF:

0.0414

Gnomad NFE

AF:

0.0252

Gnomad OTH

AF:

0.0398

GnomAD2 exomes

AF:

0.0488

AC:

4004

AN:

82008

AF XY:

0.0474

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.0807

Gnomad ASJ exome

AF:

0.0670

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.00467

Gnomad NFE exome

AF:

0.0254

Gnomad OTH exome

AF:

0.0448

GnomAD4 exome

AF:

0.0309

AC:

41282

AN:

1335008

Hom.:

911

Cov.:

AF XY:

0.0317

AC XY:

20884

AN XY:

658392

show subpopulations

African (AFR)

AF:

0.00881

AC:

237

AN:

26904

American (AMR)

AF:

0.0820

AC:

2312

AN:

28190

Ashkenazi Jewish (ASJ)

AF:

0.0665

AC:

1563

AN:

23520

East Asian (EAS)

AF:

0.109

AC:

3135

AN:

28822

South Asian (SAS)

AF:

0.0613

AC:

4536

AN:

74008

European-Finnish (FIN)

AF:

0.00571

AC:

206

AN:

36060

Middle Eastern (MID)

AF:

0.0381

AC:

169

AN:

4434

European-Non Finnish (NFE)

AF:

0.0257

AC:

27196

AN:

1057652

Other (OTH)

AF:

0.0348

AC:

1928

AN:

55418

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2679

5358

8038

10717

13396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1140

2280

3420

4560

5700

<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:

0.0302

AC:

4588

AN:

152128

Hom.:

157

Cov.:

AF XY:

0.0315

AC XY:

2343

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0114

AC:

472

AN:

41544

American (AMR)

AF:

0.0790

AC:

1207

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0703

AC:

244

AN:

3470

East Asian (EAS)

AF:

0.108

AC:

552

AN:

5126

South Asian (SAS)

AF:

0.0534

AC:

258

AN:

4828

European-Finnish (FIN)

AF:

0.00387

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0252

AC:

1716

AN:

67970

Other (OTH)

AF:

0.0398

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

229

459

688

918

1147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0233

Hom.:

Bravo

AF:

0.0342

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00519

AC:

ESP6500EA

AF:

0.0163

AC:

ExAC

AF:

0.0213

AC:

1034

Asia WGS

AF:

0.0720

AC:

247

AN:

3450

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.24

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.99

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.50

REVEL

Benign

0.21

Sift

Benign

0.14

Sift4G

Benign

0.47

Polyphen

0.0040

Vest4

0.024

MutPred

0.070

Gain of sheet (P = 0.0827);

MPC

1.7

ClinPred

0.0023

GERP RS

0.45

PromoterAI

0.0081

Neutral

(source)

Varity_R

0.055

gMVP

0.15

Mutation Taster

=96/4

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over