17-47744478-C-G

Variant names:

• chr17-47744478-C-G
• rs17250953
• NM_013351.2:c.928-4C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_013351.2(TBX21):​c.928-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,614,080 control chromosomes in the GnomAD database, including 2,006 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (155 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1851 hom.)
• Consequence: TBX21 NM_013351.2 splice_region, intron
• Scores: Splicing: ADA: 0.0005229
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 5 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):

• immunodeficiency 88

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX21	NM_013351.2	c.928-4C>G		splice_region_variant, intron_variant	Intron 4 of 5	ENST00000177694.2	NP_037483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX21	ENST00000177694.2	c.928-4C>G		splice_region_variant, intron_variant	Intron 4 of 5	1	NM_013351.2	ENSP00000177694.1

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5532 AN: 152144 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0512

GnomAD2 exomes AF: 0.0397 AC: 9974 AN: 251344 AF XY: 0.0413

Gnomad AFR exome AF: 0.00946

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0843

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0571

Gnomad OTH exome AF: 0.0527

GnomAD4 exome AF: 0.0469 AC: 68554 AN: 1461818 Hom.: 1851 Cov.: 32 AF XY: 0.0468 AC XY: 34001 AN XY: 727220

African (AFR) AF: 0.00956 AC: 320 AN: 33480

American (AMR) AF: 0.0311 AC: 1392 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0847 AC: 2215 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0232 AC: 2004 AN: 86256

European-Finnish (FIN) AF: 0.0256 AC: 1368 AN: 53420

Middle Eastern (MID) AF: 0.136 AC: 782 AN: 5768

European-Non Finnish (NFE) AF: 0.0518 AC: 57547 AN: 1111940

Other (OTH) AF: 0.0484 AC: 2921 AN: 60394

GnomAD4 genome AF: 0.0363 AC: 5532 AN: 152262 Hom.: 155 Cov.: 32 AF XY: 0.0339 AC XY: 2523 AN XY: 74456

African (AFR) AF: 0.0108 AC: 448 AN: 41552

American (AMR) AF: 0.0374 AC: 572 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 315 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4830

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10618

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0549 AC: 3734 AN: 68012

Other (OTH) AF: 0.0502 AC: 106 AN: 2112

Alfa AF: 0.0556 Hom.: 89

Bravo AF: 0.0377

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0601

EpiControl AF: 0.0610

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		1.2
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00052
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs17250953; hg19: chr17-45821844;