chr17-47733567-C-A

Variant names:

• chr17-47733567-C-A
• rs530103182
• NM_013351.2:c.113C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013351.2(TBX21):​c.113C>A​(p.Pro38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,473,260 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P38S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: TBX21 NM_013351.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.415
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18399623).

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.113C>A	p.Pro38Gln	missense	Exon 1 of 6	NP_037483.1	Q9UL17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX21	ENST00000177694.2	TSL:1 MANE Select	c.113C>A	p.Pro38Gln	missense	Exon 1 of 6	ENSP00000177694.1	Q9UL17
	TBX21	ENST00000906368.1		c.113C>A	p.Pro38Gln	missense	Exon 1 of 7	ENSP00000576427.1
	TBX21	ENST00000581328.1	TSL:2	n.143C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000378 AC: 5 AN: 1321104 Hom.: 0 Cov.: 31 AF XY: 0.00000461 AC XY: 3 AN XY: 651296

African (AFR) AF: 0.000189 AC: 5 AN: 26508

American (AMR) AF: 0.00 AC: 0 AN: 24772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22970

East Asian (EAS) AF: 0.00 AC: 0 AN: 28332

South Asian (SAS) AF: 0.00 AC: 0 AN: 72264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4178

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051912

Other (OTH) AF: 0.00 AC: 0 AN: 54768

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

African (AFR) AF: 0.000144 AC: 6 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Asthma, nasal polyps, and aspirin intolerance;C5562026:Immunodeficiency 88 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.41
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.23	N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.67	T
Polyphen		0.32	B
Vest4		0.17
MutPred		0.15		Gain of sheet (P = 0.0827)
MVP		0.19
MPC		2.2
ClinPred		0.28	T
GERP RS		0.30
PromoterAI		-0.040	Neutral
Varity_R		0.096
gMVP		0.40
Mutation Taster		=99/1	polymorphism

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: rs530103182; hg19: chr17-45810933;