rs142592809

Positions:

• chr12-114683140-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005996.4(TBX3):​c.61C>T​(p.Leu21Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00848 in 1,612,724 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (69 hom.)
• Consequence: TBX3 NM_005996.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.68

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-114683140-G-A is Benign according to our data. Variant chr12-114683140-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 307378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00641 (977/152304) while in subpopulation NFE AF= 0.0104 (706/68026). AF 95% confidence interval is 0.00974. There are 6 homozygotes in gnomad4. There are 436 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 977 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX3	NM_005996.4	c.61C>T	p.Leu21Leu	synonymous_variant	1/7	ENST00000349155.7	NP_005987.3
TBX3	NM_016569.4	c.61C>T	p.Leu21Leu	synonymous_variant	1/8		NP_057653.3
TBX3-AS1	NR_187552.1	n.343+506G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX3	ENST00000349155.7	c.61C>T	p.Leu21Leu	synonymous_variant	1/7	1	NM_005996.4	ENSP00000257567.2

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 973 AN: 152186 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00607 AC: 1503 AN: 247688 Hom.: 5 AF XY: 0.00599 AC XY: 808 AN XY: 134904

Gnomad AFR exome AF: 0.00348

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00351

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00625

GnomAD4 exome AF: 0.00869 AC: 12693 AN: 1460420 Hom.: 69 Cov.: 31 AF XY: 0.00851 AC XY: 6183 AN XY: 726404

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00633

GnomAD4 genome AF: 0.00641 AC: 977 AN: 152304 Hom.: 6 Cov.: 32 AF XY: 0.00585 AC XY: 436 AN XY: 74468

Gnomad4 AFR AF: 0.00428

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00462

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00878 Hom.: 5

Bravo AF: 0.00679

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00927

EpiControl AF: 0.00966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TBX3: BP4, BP7, BS1, BS2; TBX3-AS1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ulnar-mammary syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs142592809; hg19: chr12-115120945;