rs2240017

Positions:

• chr17-47733553-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000177694.2(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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.030 (157 hom., cov: 32)
  • Exomes 𝑓: 0.031 (911 hom.)
• Consequence: TBX21 ENST00000177694.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.991

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
TBX21	NM_013351.2	c.99C>G	p.His33Gln	missense_variant	1/6	ENST00000177694.2	NP_037483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX21	ENST00000177694.2	c.99C>G	p.His33Gln	missense_variant	1/6	1	NM_013351.2	ENSP00000177694	P1
TBX21	ENST00000581328.1	n.129C>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4577 AN: 152020 Hom.: 156 Cov.: 32

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

GnomAD3 exomes AF: 0.0488 AC: 4004 AN: 82008 Hom.: 164 AF XY: 0.0474 AC XY: 2231 AN XY: 47062

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 SAS exome AF: 0.0597

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.: 31 AF XY: 0.0317 AC XY: 20884 AN XY: 658392

Gnomad4 AFR exome AF: 0.00881

Gnomad4 AMR exome AF: 0.0820

Gnomad4 ASJ exome AF: 0.0665

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.0613

Gnomad4 FIN exome AF: 0.00571

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0348

GnomAD4 genome AF: 0.0302 AC: 4588 AN: 152128 Hom.: 157 Cov.: 32 AF XY: 0.0315 AC XY: 2343 AN XY: 74366

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0790

Gnomad4 ASJ AF: 0.0703

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.0534

Gnomad4 FIN AF: 0.00387

Gnomad4 NFE AF: 0.0252

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0233 Hom.: 12

Bravo AF: 0.0342

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00519 AC: 12

ESP6500EA AF: 0.0163 AC: 86

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

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.58
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.92	P
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.21
Sift	Benign	0.14	T
Sift4G	Benign	0.47	T
Polyphen		0.0040	B
Vest4		0.024
MutPred		0.070		Gain of sheet (P = 0.0827);
MPC		1.7
ClinPred		0.0023	T
GERP RS		0.45
Varity_R		0.055
gMVP		0.15

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

Other links and lift over

dbSNP: rs2240017; hg19: chr17-45810919; COSMIC: COSV51596141;