Genetic Variant TBX21:p.Pro59Ser (chr17-47733629-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_013351.2(TBX21):c.175C>T(p.Pro59Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,449,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

TBX21
NM_013351.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.482

Publications

0 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):

asthma, nasal polyps, and aspirin intolerance
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia
immunodeficiency 88
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

TBX21 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17190066).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013351.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX21	NM_013351.2	MANE Select	c.175C>T	p.Pro59Ser	missense	Exon 1 of 6	NP_037483.1	Q9UL17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX21	ENST00000177694.2	TSL:1 MANE Select	c.175C>T	p.Pro59Ser	missense	Exon 1 of 6	ENSP00000177694.1	Q9UL17
TBX21	ENST00000906368.1		c.175C>T	p.Pro59Ser	missense	Exon 1 of 7	ENSP00000576427.1
TBX21	ENST00000581328.1	TSL:2	n.205C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

151822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000334

AC:

AN:

59856

AF XY:

0.0000286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000904

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000568

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1298016

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

639332

show subpopulations

African (AFR)

AF:

0.000730

AC:

AN:

26036

American (AMR)

AF:

0.0000457

AC:

AN:

21904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21750

East Asian (EAS)

AF:

0.0000360

AC:

AN:

27814

South Asian (SAS)

AF:

0.00

AC:

AN:

68332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3820

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1038834

Other (OTH)

AF:

0.0000931

AC:

AN:

53710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000184

AC:

AN:

151822

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74148

show subpopulations

African (AFR)

AF:

0.000628

AC:

AN:

41384

American (AMR)

AF:

0.0000656

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67878

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000285

Hom.:

Bravo

AF:

0.000287

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.50

CADD

Benign

2.0

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.25

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.55

PhyloP100

-0.48

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.94

REVEL

Benign

0.14

Sift

Benign

0.27

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.038

MutPred

0.23

Gain of glycosylation at P59 (P = 0.0114)

MVP

0.30

MPC

1.7

ClinPred

0.0087

GERP RS

-0.29

PromoterAI

0.0020

Neutral

(source)

Varity_R

0.032

gMVP

0.26

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over