12-114682915-C-G

Variant names:

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

Variant summary

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

The NM_005996.4(TBX3):​c.286G>C​(p.Glu96Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E96K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX3 NM_005996.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 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-AS1 (HGNC:55471): (TBX3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.286G>C	p.Glu96Gln	missense	Exon 1 of 7	NP_005987.3
	TBX3	NM_016569.4		c.286G>C	p.Glu96Gln	missense	Exon 1 of 8	NP_057653.3
	TBX3-AS1	NR_187552.1		n.343+281C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX3	ENST00000349155.7	TSL:1 MANE Select	c.286G>C	p.Glu96Gln	missense	Exon 1 of 7	ENSP00000257567.2	O15119-2
	TBX3	ENST00000257566.7	TSL:1	c.286G>C	p.Glu96Gln	missense	Exon 1 of 8	ENSP00000257566.3	O15119-1
	TBX3	ENST00000552054.1	TSL:2	n.520G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.45
Sift	Benign	0.072	T
Sift4G	Benign	0.24	T
Polyphen		0.99	D
Vest4		0.45
MutPred		0.28		Gain of loop (P = 0.024)
MVP		0.79
MPC		2.1
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.46
gMVP		0.61
Mutation Taster		=82/18	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: rs1869001823; hg19: chr12-115120720;