12-114670331-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005996.4(TBX3):c.*1510A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 223,952 control chromosomes in the GnomAD database, including 7,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4986 hom., cov: 32)
  • Exomes 𝑓: 0.27 (2716 hom.)
• Consequence: TBX3 NM_005996.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.950

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-114670331-T-C is Benign according to our data. Variant chr12-114670331-T-C is described in ClinVar as [Benign]. Clinvar id is 307325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX3	NM_005996.4	c.*1510A>G		3_prime_UTR_variant	7/7	ENST00000349155.7
TBX3	NM_016569.4	c.*1510A>G		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX3	ENST00000349155.7	c.*1510A>G		3_prime_UTR_variant	7/7	1	NM_005996.4	P4
TBX3	ENST00000257566.7	c.*1510A>G		3_prime_UTR_variant	8/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35436 AN: 151908 Hom.: 4976 Cov.: 32

Gnomad AFR AF: 0.0867

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.267 AC: 19222 AN: 71926 Hom.: 2716 Cov.: 0 AF XY: 0.266 AC XY: 8817 AN XY: 33180

Gnomad4 AFR exome AF: 0.0870

Gnomad4 AMR exome AF: 0.383

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.339

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.233 AC: 35458 AN: 152026 Hom.: 4986 Cov.: 32 AF XY: 0.239 AC XY: 17746 AN XY: 74318

Gnomad4 AFR AF: 0.0868

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.268

Alfa AF: 0.248 Hom.: 2000

Bravo AF: 0.243

Asia WGS AF: 0.298 AC: 1034 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ulnar-mammary syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
Dann	Benign	0.88

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: rs1061657; hg19: chr12-115108136;