12-114671094-C-T

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.*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, single submitter B:1
• Conservation: PhyloP100: 0.0100

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=-0.83).
• BP6: Variant 12-114671094-C-T is Benign according to our data. Variant chr12-114671094-C-T is described in ClinVar as [Benign]. Clinvar id is 307335.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX3	NM_005996.4	c.*747G>A		3_prime_UTR_variant	7/7	ENST00000349155.7
TBX3	NM_016569.4	c.*747G>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX3	ENST00000349155.7	c.*747G>A		3_prime_UTR_variant	7/7	1	NM_005996.4	P4
TBX3	ENST00000257566.7	c.*747G>A		3_prime_UTR_variant	8/8	1		A1

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

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.0474

Gnomad4 ASJ exome AF: 0.0395

Gnomad4 EAS exome AF: 0.0984

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.0578

Gnomad4 OTH exome AF: 0.0503

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

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.0463

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.0726

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.0657

Gnomad4 OTH AF: 0.0458

Alfa AF: 0.0633 Hom.: 83

Bravo AF: 0.0449

Asia WGS AF: 0.0860 AC: 297 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	-0.83
Cadd	Benign	1.5
Dann	Benign	0.52

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: rs3741695; hg19: chr12-115108899;