12-114682915-C-T

Variant names:

• chr12-114682915-C-T
• rs1869001823
• NM_005996.4:c.286G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005996.4(TBX3):​c.286G>A​(p.Glu96Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TBX3 NM_005996.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.57

Genes affected

TBX3 (HGNC:11602): (T-box transcription factor 3) 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 protein is a transcriptional repressor and is thought to play a role in the anterior/posterior axis of the tetrapod forelimb. Mutations in this gene cause ulnar-mammary syndrome, affecting limb, apocrine gland, tooth, hair, and genital development. Alternative splicing of this gene results in three transcript variants encoding different isoforms; however, the full length nature of one variant has not been determined. [provided by RefSeq, Jul 2008]

TBX3-AS1 (HGNC:55471): (TBX3 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX3	NM_005996.4	c.286G>A	p.Glu96Lys	missense_variant	Exon 1 of 7	ENST00000349155.7	NP_005987.3
TBX3	NM_016569.4	c.286G>A	p.Glu96Lys	missense_variant	Exon 1 of 8		NP_057653.3
TBX3-AS1	NR_187552.1	n.343+281C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX3	ENST00000349155.7	c.286G>A	p.Glu96Lys	missense_variant	Exon 1 of 7	1	NM_005996.4	ENSP00000257567.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

TBX3-related disorder Uncertain:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TBX3 c.286G>A variant is predicted to result in the amino acid substitution p.Glu96Lys. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.65
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.54
MutPred		0.41		Gain of ubiquitination at E96 (P = 0.001);Gain of ubiquitination at E96 (P = 0.001);
MVP		0.78
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.71
gMVP		0.69

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: rs1869001823; hg19: chr12-115120720;