12-114674452-G-C

Variant names:

• chr12-114674452-G-C
• NM_005996.4:c.1423C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005996.4(TBX3):​c.1423C>G​(p.Gln475Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000718 in 1,393,158 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q475R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TBX3 NM_005996.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36303082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX3	NM_005996.4	c.1423C>G	p.Gln475Glu	missense_variant	Exon 6 of 7	ENST00000349155.7	NP_005987.3
TBX3	NM_016569.4	c.1483C>G	p.Gln495Glu	missense_variant	Exon 7 of 8		NP_057653.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX3	ENST00000349155.7	c.1423C>G	p.Gln475Glu	missense_variant	Exon 6 of 7	1	NM_005996.4	ENSP00000257567.2
TBX3	ENST00000257566.7	c.1483C>G	p.Gln495Glu	missense_variant	Exon 7 of 8	1		ENSP00000257566.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393158 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 686778

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: 0.0000212

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.57	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	.;L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.28
Sift	Benign	0.079	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.0	B;B
Vest4		0.54
MutPred		0.27		.;Gain of disorder (P = 0.238);
MVP		0.57
MPC		0.52
ClinPred		0.72	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-115112257;