12-114674749-A-G

Variant names:

• chr12-114674749-A-G
• rs78115331
• NM_005996.4:c.1126T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005996.4(TBX3):​c.1126T>C​(p.Ser376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S376T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBX3 NM_005996.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.892
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• ulnar-mammary syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31998152).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005996.4. 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
	TBX3	NM_005996.4	MANE Select	c.1126T>C	p.Ser376Pro	missense	Exon 6 of 7	NP_005987.3
	TBX3	NM_016569.4		c.1186T>C	p.Ser396Pro	missense	Exon 7 of 8	NP_057653.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX3	ENST00000349155.7	TSL:1 MANE Select	c.1126T>C	p.Ser376Pro	missense	Exon 6 of 7	ENSP00000257567.2	O15119-2
	TBX3	ENST00000257566.7	TSL:1	c.1186T>C	p.Ser396Pro	missense	Exon 7 of 8	ENSP00000257566.3	O15119-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1442470 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717106

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 42730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 39220

South Asian (SAS) AF: 0.00 AC: 0 AN: 84222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107090

Other (OTH) AF: 0.00 AC: 0 AN: 59860

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
PhyloP100		0.89
Varity_R		0.22
gMVP		0.40
Mutation Taster		=77/23	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs78115331; hg19: chr12-115112554; COSMIC: COSV57475836;