rs117097130

chr6-166160858-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001366285.2(TBXT):c.1016C>T(p.Ala339Val) variant causes a missense change. The variant allele was found at a frequency of 0.00614 in 1,614,114 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A339A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (35 hom.)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.51

Genes affected

TBXT (HGNC:11515): (T-box transcription factor T) The protein encoded by this gene is an embryonic nuclear transcription factor that binds to a specific DNA element, the palindromic T-site. It binds through a region in its N-terminus, called the T-box, and effects transcription of genes required for mesoderm formation and differentiation. The protein is localized to notochord-derived cells. Variation in this gene was associated with susceptibility to neural tube defects and chordoma. A mutation in this gene was found in a family with sacral agenesis with vertebral anomalies. [provided by RefSeq, Sep 2018]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068078935).
• BP6: Variant 6-166160858-G-A is Benign according to our data. Variant chr6-166160858-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 715 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXT	NM_001366285.2	c.1016C>T	p.Ala339Val	missense_variant	7/8	ENST00000366876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXT	ENST00000366876.7	c.1016C>T	p.Ala339Val	missense_variant	7/8	1	NM_001366285.2	P4
TBXT	ENST00000366871.7	c.839C>T	p.Ala280Val	missense_variant	7/8	1
TBXT	ENST00000296946.6	c.1013C>T	p.Ala338Val	missense_variant	8/9	5		A1

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 715 AN: 152192 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00686

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00503 AC: 1266 AN: 251456 Hom.: 9 AF XY: 0.00517 AC XY: 703 AN XY: 135900

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.00699

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00629 AC: 9200 AN: 1461804 Hom.: 35 Cov.: 33 AF XY: 0.00621 AC XY: 4515 AN XY: 727198

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00440

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.00718

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.00469 AC: 715 AN: 152310 Hom.: 5 Cov.: 33 AF XY: 0.00498 AC XY: 371 AN XY: 74482

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.00686

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00664 Hom.: 9

Bravo AF: 0.00383

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00483 AC: 587

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00670

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 08, 2017

- -

TBXT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T;T;T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.11	T;T;T
Sift4G	Uncertain	0.052	T;T;.
Polyphen		0.0040	B;.;.
Vest4		0.73
MVP		0.84
MPC		0.17
ClinPred		0.015	T
GERP RS		4.0
Varity_R		0.069
gMVP		0.25

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: rs117097130; hg19: chr6-166574346;