rs1060505020

Positions:

• chr12-114674452-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_005996.4(TBX3):​c.1423C>T​(p.Gln475Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX3 NM_005996.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.09

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-114674452-G-A is Pathogenic according to our data. Variant chr12-114674452-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 417720.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.1423C>T	p.Gln475Ter	stop_gained	6/7	ENST00000349155.7
TBX3	NM_016569.4	c.1483C>T	p.Gln495Ter	stop_gained	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX3	ENST00000349155.7	c.1423C>T	p.Gln475Ter	stop_gained	6/7	1	NM_005996.4	P4
TBX3	ENST00000257566.7	c.1483C>T	p.Gln495Ter	stop_gained	7/8	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ulnar-mammary syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Apr 16, 2021	PVS1, PS4_moderate, PM2 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2020

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1423C>T (p.Q475*) alteration, located in coding exon 6 of the TBX3 gene, consists of a C to T substitution at nucleotide position 1423. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 475. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the TBX3 c.1423C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported in one family with UMS and variable severity. Twin boys presented with digital anomalies, ankyloglossia, short stature, and flared eyebrows. Twin I had additional findings including bifid uvula, left simple ear, hypertelorism, up-slanting palpebral fissures, hypoplastic and underpigmented nipples, and a bifid scrotum. Twin II had lack of sexual development at age15 years.The father was more mildly affected with digital anomalies (Tanteles, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A
Vest4		0.43
GERP RS		5.2

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: rs1060505020; hg19: chr12-115112257;