chr12-114670556-T-C

Position:

• chr12-114670556-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_005996.4(TBX3):​c.*1285A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4888 hom., cov: 30)
  • Exomes 𝑓: 0.22 (1656 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBX3 NM_005996.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.818

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-114670556-T-C is Benign according to our data. Variant chr12-114670556-T-C is described in ClinVar as [Benign]. Clinvar id is 307329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX3	NM_005996.4	c.*1285A>G		3_prime_UTR_variant	7/7	ENST00000349155.7
TBX3	NM_016569.4	c.*1285A>G		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX3	ENST00000349155.7	c.*1285A>G		3_prime_UTR_variant	7/7	1	NM_005996.4	P4
TBX3	ENST00000257566.7	c.*1285A>G		3_prime_UTR_variant	8/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 34125 AN: 147686 Hom.: 4879 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.268

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.220 AC: 13918 AN: 63204 Hom.: 1656 Cov.: 0 AF XY: 0.220 AC XY: 6435 AN XY: 29272

Gnomad4 AFR exome AF: 0.0578

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.328

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.208

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.231 AC: 34147 AN: 147800 Hom.: 4888 Cov.: 30 AF XY: 0.236 AC XY: 16963 AN XY: 71904

Gnomad4 AFR AF: 0.0817

Gnomad4 AMR AF: 0.381

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.271

Alfa AF: 0.269 Hom.: 2425

Bravo AF: 0.250

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.85
CADD	Benign	6.8
DANN	Benign	0.67

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: rs1061651; hg19: chr12-115108361; COSMIC: COSV57474296;