12-114670577-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005996.4(TBX3):c.*1264C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 219,438 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: TBX3 NM_005996.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.02

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=-0.84).
• BP6: Variant 12-114670577-G-C is Benign according to our data. Variant chr12-114670577-G-C is described in ClinVar as [Benign]. Clinvar id is 307330.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00602 (891/147896) while in subpopulation AFR AF= 0.0203 (832/40992). AF 95% confidence interval is 0.0192. There are 9 homozygotes in gnomad4. There are 388 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 892 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX3	NM_005996.4	c.*1264C>G		3_prime_UTR_variant	7/7	ENST00000349155.7
TBX3	NM_016569.4	c.*1264C>G		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX3	ENST00000349155.7	c.*1264C>G		3_prime_UTR_variant	7/7	1	NM_005996.4	P4
TBX3	ENST00000257566.7	c.*1264C>G		3_prime_UTR_variant	8/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 892 AN: 147798 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00234

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.000207

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.00749

GnomAD4 exome AF: 0.00147 AC: 105 AN: 71542 Hom.: 0 Cov.: 0 AF XY: 0.00133 AC XY: 44 AN XY: 33042

Gnomad4 AFR exome AF: 0.0222

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.000889

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.00218

GnomAD4 genome AF: 0.00602 AC: 891 AN: 147896 Hom.: 9 Cov.: 32 AF XY: 0.00541 AC XY: 388 AN XY: 71704

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.00234

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000149

Gnomad4 OTH AF: 0.00743

Alfa AF: 0.00381 Hom.: 0

Bravo AF: 0.00681

Asia WGS AF: 0.00144 AC: 5 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 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	-0.84
Cadd	Benign	9.8
Dann	Benign	0.44

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: rs146480305; hg19: chr12-115108382;