12-114671418-C-G

Position:

• chr12-114671418-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005996.4(TBX3):​c.*423G>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 0.324 in 289,270 control chromosomes in the GnomAD database, including 16,510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9140 hom., cov: 33)
  • Exomes 𝑓: 0.31 (7370 hom.)
• Consequence: TBX3 NM_005996.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0240

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-114671418-C-G is Benign according to our data. Variant chr12-114671418-C-G is described in ClinVar as [Benign]. Clinvar id is 307341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX3	NM_005996.4	c.*423G>C		3_prime_UTR_variant	7/7	ENST00000349155.7
TBX3	NM_016569.4	c.*423G>C		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX3	ENST00000349155.7	c.*423G>C		3_prime_UTR_variant	7/7	1	NM_005996.4	P4
TBX3	ENST00000257566.7	c.*423G>C		3_prime_UTR_variant	8/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51513 AN: 151850 Hom.: 9110 Cov.: 33

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.343

GnomAD4 exome AF: 0.307 AC: 42198 AN: 137302 Hom.: 7370 Cov.: 0 AF XY: 0.303 AC XY: 19968 AN XY: 65980

Gnomad4 AFR exome AF: 0.366

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.505

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.309

GnomAD4 genome AF: 0.340 AC: 51597 AN: 151968 Hom.: 9140 Cov.: 33 AF XY: 0.343 AC XY: 25476 AN XY: 74256

Gnomad4 AFR AF: 0.383

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.556

Gnomad4 SAS AF: 0.325

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.346

Alfa AF: 0.297 Hom.: 915

Bravo AF: 0.357

Asia WGS AF: 0.420 AC: 1458 AN: 3478

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 12, 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	8.6
DANN	Benign	0.59

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: rs3741698; hg19: chr12-115109223;