12-114670331-T-C

Variant names:

• chr12-114670331-T-C
• rs1061657
• NM_005996.4:c.*1510A>G

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.950
• Publications: 18 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: Benign. The variant received -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 VariationId 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.

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.*1510A>G		3_prime_UTR	Exon 7 of 7	NP_005987.3
	TBX3	NM_016569.4		c.*1510A>G		3_prime_UTR	Exon 8 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.*1510A>G		3_prime_UTR	Exon 7 of 7	ENSP00000257567.2	O15119-2
	TBX3	ENST00000257566.7	TSL:1	c.*1510A>G		3_prime_UTR	Exon 8 of 8	ENSP00000257566.3	O15119-1

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

African (AFR) AF: 0.0870 AC: 303 AN: 3484

American (AMR) AF: 0.383 AC: 828 AN: 2164

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 1293 AN: 4532

East Asian (EAS) AF: 0.339 AC: 3454 AN: 10186

South Asian (SAS) AF: 0.204 AC: 126 AN: 618

European-Finnish (FIN) AF: 0.250 AC: 12 AN: 48

Middle Eastern (MID) AF: 0.285 AC: 126 AN: 442

European-Non Finnish (NFE) AF: 0.259 AC: 11481 AN: 44404

Other (OTH) AF: 0.264 AC: 1599 AN: 6048

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

African (AFR) AF: 0.0868 AC: 3602 AN: 41498

American (AMR) AF: 0.394 AC: 6029 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1053 AN: 3468

East Asian (EAS) AF: 0.424 AC: 2185 AN: 5156

South Asian (SAS) AF: 0.229 AC: 1099 AN: 4802

European-Finnish (FIN) AF: 0.241 AC: 2544 AN: 10548

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17954 AN: 67952

Other (OTH) AF: 0.268 AC: 567 AN: 2114

Alfa AF: 0.255 Hom.: 4029

Bravo AF: 0.243

Asia WGS AF: 0.298 AC: 1034 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Ulnar-mammary syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism (auto)

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: rs1061657; hg19: chr12-115108136;