12-114671094-C-T

Variant names:

• chr12-114671094-C-T
• rs3741695
• NM_005996.4:c.*747G>A

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.*747G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 210,176 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (333 hom., cov: 32)
  • Exomes 𝑓: 0.060 (112 hom.)
• Consequence: TBX3 NM_005996.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0100
• Publications: 2 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=-0.83).
• BP6: Variant 12-114671094-C-T is Benign according to our data. Variant chr12-114671094-C-T is described in ClinVar as Benign. ClinVar VariationId is 307335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 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.*747G>A		3_prime_UTR	Exon 7 of 7	NP_005987.3
	TBX3	NM_016569.4		c.*747G>A		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.*747G>A		3_prime_UTR	Exon 7 of 7	ENSP00000257567.2	O15119-2
	TBX3	ENST00000257566.7	TSL:1	c.*747G>A		3_prime_UTR	Exon 8 of 8	ENSP00000257566.3	O15119-1

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8373 AN: 152022 Hom.: 334 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.0730

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0657

Gnomad OTH AF: 0.0463

GnomAD4 exome AF: 0.0603 AC: 3499 AN: 58036 Hom.: 112 Cov.: 0 AF XY: 0.0600 AC XY: 1619 AN XY: 26970

African (AFR) AF: 0.0105 AC: 28 AN: 2674

American (AMR) AF: 0.0474 AC: 80 AN: 1686

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 147 AN: 3718

East Asian (EAS) AF: 0.0984 AC: 823 AN: 8366

South Asian (SAS) AF: 0.112 AC: 57 AN: 508

European-Finnish (FIN) AF: 0.140 AC: 52 AN: 372

Middle Eastern (MID) AF: 0.0449 AC: 16 AN: 356

European-Non Finnish (NFE) AF: 0.0578 AC: 2053 AN: 35524

Other (OTH) AF: 0.0503 AC: 243 AN: 4832

GnomAD4 genome AF: 0.0550 AC: 8371 AN: 152140 Hom.: 333 Cov.: 32 AF XY: 0.0585 AC XY: 4348 AN XY: 74368

African (AFR) AF: 0.0159 AC: 659 AN: 41500

American (AMR) AF: 0.0463 AC: 707 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3472

East Asian (EAS) AF: 0.0726 AC: 376 AN: 5178

South Asian (SAS) AF: 0.116 AC: 559 AN: 4814

European-Finnish (FIN) AF: 0.126 AC: 1328 AN: 10560

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0657 AC: 4470 AN: 68016

Other (OTH) AF: 0.0458 AC: 97 AN: 2116

Alfa AF: 0.0621 Hom.: 83

Bravo AF: 0.0449

Asia WGS AF: 0.0860 AC: 297 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		0.010
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: rs3741695; hg19: chr12-115108899;