12-114670617-A-G

Position:

• chr12-114670617-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005996.4(TBX3):​c.*1224T>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 0.00313 in 217,674 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (0 hom.)
• Consequence: TBX3 NM_005996.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0400

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-114670617-A-G is Benign according to our data. Variant chr12-114670617-A-G is described in ClinVar as [Benign]. Clinvar id is 307331.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX3	NM_005996.4	c.*1224T>C		3_prime_UTR_variant	7/7	ENST00000349155.7
TBX3	NM_016569.4	c.*1224T>C		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX3	ENST00000349155.7	c.*1224T>C		3_prime_UTR_variant	7/7	1	NM_005996.4	P4
TBX3	ENST00000257566.7	c.*1224T>C		3_prime_UTR_variant	8/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 425 AN: 151340 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00273

Gnomad ASJ AF: 0.00956

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00458

Gnomad FIN AF: 0.000957

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00417

Gnomad OTH AF: 0.00434

GnomAD4 exome AF: 0.00390 AC: 258 AN: 66222 Hom.: 0 Cov.: 0 AF XY: 0.00352 AC XY: 108 AN XY: 30710

Gnomad4 AFR exome AF: 0.000298

Gnomad4 AMR exome AF: 0.00703

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00366

Gnomad4 FIN exome AF: 0.00219

Gnomad4 NFE exome AF: 0.00430

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.00280 AC: 424 AN: 151452 Hom.: 4 Cov.: 32 AF XY: 0.00261 AC XY: 193 AN XY: 73942

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.00266

Gnomad4 ASJ AF: 0.00956

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00459

Gnomad4 FIN AF: 0.000957

Gnomad4 NFE AF: 0.00417

Gnomad4 OTH AF: 0.00429

Alfa AF: 0.00339 Hom.: 0

Bravo AF: 0.00282

Asia WGS AF: 0.00202 AC: 7 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	-0.84
CADD	Benign	0.41
DANN	Benign	0.75

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: rs141045947; hg19: chr12-115108422;