12-114670529-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005996.4(TBX3):c.*1312T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 226,114 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (24 hom.)
• Consequence: TBX3 NM_005996.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-114670529-A-G is Benign according to our data. Variant chr12-114670529-A-G is described in ClinVar as [Benign]. Clinvar id is 307328.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX3	NM_005996.4	c.*1312T>C		3_prime_UTR_variant	7/7	ENST00000349155.7
TBX3	NM_016569.4	c.*1312T>C		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX3	ENST00000349155.7	c.*1312T>C		3_prime_UTR_variant	7/7	1	NM_005996.4	P4
TBX3	ENST00000257566.7	c.*1312T>C		3_prime_UTR_variant	8/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152172 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0405

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00878 AC: 648 AN: 73824 Hom.: 24 Cov.: 0 AF XY: 0.00911 AC XY: 310 AN XY: 34046

Gnomad4 AFR exome AF: 0.000277

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0600

Gnomad4 SAS exome AF: 0.00469

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152290 Hom.: 7 Cov.: 33 AF XY: 0.00435 AC XY: 324 AN XY: 74470

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0408

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00201

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ulnar-mammary syndrome Benign:1

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	-0.93
Cadd	Benign	0.21
Dann	Benign	0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs77412687; hg19: chr12-115108334;