6-166167659-T-C

Variant names:

• chr6-166167659-T-C
• rs3099266
• NM_001366285.2:c.-68A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001366285.2(TBXT):​c.-68A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,530,136 control chromosomes in the GnomAD database, including 286,021 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (34063 hom., cov: 31)
  • Exomes 𝑓: 0.60 (251958 hom.)
• Consequence: TBXT NM_001366285.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• Publications: 26 publications found

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]

TBXT Gene-Disease associations (from GenCC):

• chordoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBXT	NM_001366285.2	c.-68A>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000366876.7	NP_001353214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBXT	ENST00000366876.7	c.-68A>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_001366285.2	ENSP00000355841.3
TBXT	ENST00000366871.7	c.-68A>G		5_prime_UTR_variant	Exon 2 of 8	1		ENSP00000355836.3
TBXT	ENST00000296946.6	c.-68A>G		5_prime_UTR_variant	Exon 2 of 9	5		ENSP00000296946.2
TBXT	ENST00000461348.2	c.-68A>G		5_prime_UTR_variant	Exon 2 of 6	5		ENSP00000453512.1

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100317 AN: 151792 Hom.: 34016 Cov.: 31

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.605

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.668

GnomAD4 exome AF: 0.602 AC: 830192 AN: 1378226 Hom.: 251958 Cov.: 30 AF XY: 0.602 AC XY: 409437 AN XY: 680628

African (AFR) AF: 0.831 AC: 26108 AN: 31432

American (AMR) AF: 0.636 AC: 22686 AN: 35656

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 16597 AN: 25132

East Asian (EAS) AF: 0.735 AC: 26242 AN: 35694

South Asian (SAS) AF: 0.626 AC: 49549 AN: 79096

European-Finnish (FIN) AF: 0.534 AC: 18490 AN: 34642

Middle Eastern (MID) AF: 0.638 AC: 3183 AN: 4986

European-Non Finnish (NFE) AF: 0.588 AC: 630961 AN: 1073966

Other (OTH) AF: 0.631 AC: 36376 AN: 57622

GnomAD4 genome AF: 0.661 AC: 100426 AN: 151910 Hom.: 34063 Cov.: 31 AF XY: 0.656 AC XY: 48676 AN XY: 74210

African (AFR) AF: 0.821 AC: 34047 AN: 41486

American (AMR) AF: 0.624 AC: 9531 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2323 AN: 3468

East Asian (EAS) AF: 0.757 AC: 3838 AN: 5072

South Asian (SAS) AF: 0.628 AC: 3017 AN: 4802

European-Finnish (FIN) AF: 0.510 AC: 5386 AN: 10564

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.592 AC: 40177 AN: 67920

Other (OTH) AF: 0.671 AC: 1418 AN: 2114

Alfa AF: 0.610 Hom.: 45037

Bravo AF: 0.678

Asia WGS AF: 0.749 AC: 2606 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.5
DANN	Benign	0.64
PhyloP100		-0.046
PromoterAI		0.0042	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3099266; hg19: chr6-166581147;