chr12-114682937-C-G

Variant names:

• chr12-114682937-C-G
• rs1460980304
• NM_005996.4:c.264G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005996.4(TBX3):​c.264G>C​(p.Arg88Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBX3 NM_005996.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX3	NM_005996.4	c.264G>C	p.Arg88Ser	missense_variant	Exon 1 of 7	ENST00000349155.7	NP_005987.3
TBX3	NM_016569.4	c.264G>C	p.Arg88Ser	missense_variant	Exon 1 of 8		NP_057653.3
TBX3-AS1	NR_187552.1	n.343+303C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX3	ENST00000349155.7	c.264G>C	p.Arg88Ser	missense_variant	Exon 1 of 7	1	NM_005996.4	ENSP00000257567.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ulnar-mammary syndrome Uncertain:1

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 88 of the TBX3 protein (p.Arg88Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TBX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1394632). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.043	D;D
Polyphen		1.0	D;P
Vest4		0.72
MutPred		0.29		Gain of phosphorylation at R88 (P = 0.0317);Gain of phosphorylation at R88 (P = 0.0317);
MVP		0.82
MPC		2.2
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.82

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: rs1460980304; hg19: chr12-115120742;