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17-47733780-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013351.2(TBX21):c.326C>G(p.Ala109Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,543,306 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

TBX21
NM_013351.2 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.51
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0069426894).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TBX21NM_013351.2 linkuse as main transcriptc.326C>G p.Ala109Gly missense_variant 1/6 ENST00000177694.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TBX21ENST00000177694.2 linkuse as main transcriptc.326C>G p.Ala109Gly missense_variant 1/61 NM_013351.2 P1
TBX21ENST00000581328.1 linkuse as main transcriptn.356C>G non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
AF:
0.000941
AC:
143
AN:
152010
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00807
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00310
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00134
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.00112
AC:
158
AN:
140536
Hom.:
1
AF XY:
0.00126
AC XY:
98
AN XY:
77592
show subpopulations
Gnomad AFR exome
AF:
0.000565
Gnomad AMR exome
AF:
0.0000889
Gnomad ASJ exome
AF:
0.00650
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00141
Gnomad FIN exome
AF:
0.000126
Gnomad NFE exome
AF:
0.00121
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.00122
AC:
1701
AN:
1391184
Hom.:
2
Cov.:
31
AF XY:
0.00126
AC XY:
866
AN XY:
687216
show subpopulations
Gnomad4 AFR exome
AF:
0.000231
Gnomad4 AMR exome
AF:
0.0000884
Gnomad4 ASJ exome
AF:
0.00585
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00124
Gnomad4 FIN exome
AF:
0.000104
Gnomad4 NFE exome
AF:
0.00127
Gnomad4 OTH exome
AF:
0.00118
GnomAD4 genome
AF:
0.000940
AC:
143
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.00102
AC XY:
76
AN XY:
74396
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00807
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00310
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00134
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.00116
Hom.:
1
Bravo
AF:
0.000684
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000814
AC:
6
ExAC
AF:
0.000657
AC:
73

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Asthma, nasal polyps, and aspirin intolerance Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoAug 15, 2019TBX21 NM_013351.1 exon1 p.Ala109Gly (c.326C>G): This variant has not been reported in the literature but is present in 0.1% (32/22742) of South Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-45811146-C-G). This variant amino acid Glycine (Gly) is present in two species (Black flying fox, Megabat) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Asthma, nasal polyps, and aspirin intolerance;C5562026:Immunodeficiency 88 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021TBX21 NM_013351.1 exon1 p.Ala109Gly (c.326C>G): This variant has not been reported in the literature but is present in 0.1% (32/22742) of South Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-45811146-C-G). This variant amino acid Glycine (Gly) is present in two species (Black flying fox, Megabat) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.42
Cadd
Benign
15
Dann
Benign
0.65
DEOGEN2
Benign
0.17
T
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.37
T
M_CAP
Pathogenic
0.37
D
MetaRNN
Benign
0.0069
T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
0.81
L
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
0.27
N
REVEL
Benign
0.23
Sift
Benign
0.34
T
Sift4G
Benign
0.69
T
Polyphen
0.0020
B
Vest4
0.093
MVP
0.52
MPC
1.7
ClinPred
0.0043
T
GERP RS
2.5
Varity_R
0.092
gMVP
0.33

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs377743321; hg19: chr17-45811146; COSMIC: COSV99456447; API