6-166158524-C-T

Variant names:

• chr6-166158524-C-T
• rs35292451
• NM_001366285.2:c.1102G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001366285.2(TBXT):​c.1102G>A​(p.Val368Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,603,094 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V368L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0330
• Publications: 3 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, LIMITED Submitted by: PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044189095).
• BP6: Variant 6-166158524-C-T is Benign according to our data. Variant chr6-166158524-C-T is described in ClinVar as Benign. ClinVar VariationId is 776183.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1766/152336) while in subpopulation AFR AF = 0.0409 (1701/41574). AF 95% confidence interval is 0.0393. There are 45 homozygotes in GnomAd4. There are 826 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366285.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBXT	NM_001366285.2	MANE Select	c.1102G>A	p.Val368Met	missense	Exon 8 of 8	NP_001353214.1	J3KP65
	TBXT	NM_001366286.2		c.1102G>A	p.Val368Met	missense	Exon 9 of 9	NP_001353215.1	J3KP65
	TBXT	NM_003181.4		c.1099G>A	p.Val367Met	missense	Exon 9 of 9	NP_003172.1	O15178-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBXT	ENST00000366876.7	TSL:1 MANE Select	c.1102G>A	p.Val368Met	missense	Exon 8 of 8	ENSP00000355841.3	J3KP65
	TBXT	ENST00000366871.7	TSL:1	c.925G>A	p.Val309Met	missense	Exon 8 of 8	ENSP00000355836.3	O15178-2
	TBXT	ENST00000296946.6	TSL:5	c.1099G>A	p.Val367Met	missense	Exon 9 of 9	ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1765 AN: 152218 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00293 AC: 711 AN: 242766 AF XY: 0.00219

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000486

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.000508

GnomAD4 exome AF: 0.00125 AC: 1807 AN: 1450758 Hom.: 37 Cov.: 34 AF XY: 0.00109 AC XY: 781 AN XY: 719468

African (AFR) AF: 0.0450 AC: 1497 AN: 33260

American (AMR) AF: 0.00137 AC: 61 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85948

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52738

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5724

European-Non Finnish (NFE) AF: 0.0000870 AC: 96 AN: 1103698

Other (OTH) AF: 0.00219 AC: 131 AN: 59754

GnomAD4 genome AF: 0.0116 AC: 1766 AN: 152336 Hom.: 45 Cov.: 33 AF XY: 0.0111 AC XY: 826 AN XY: 74482

African (AFR) AF: 0.0409 AC: 1701 AN: 41574

American (AMR) AF: 0.00320 AC: 49 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00368 Hom.: 6

Bravo AF: 0.0127

ESP6500AA AF: 0.0341 AC: 150

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00350 AC: 424

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.058
DANN	Benign	0.16
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.033
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.30
Sift	Benign	0.48	T
Sift4G	Benign	0.60	T
Polyphen		0.0030	B
Vest4		0.051
MVP		0.42
MPC		0.16
ClinPred		0.000047	T
GERP RS		-1.5
Varity_R		0.023
gMVP		0.19
Mutation Taster		=100/0	polymorphism

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: rs35292451; hg19: chr6-166572012; COSMIC: COSV51619349;