6-166162299-C-T

Variant names:

• chr6-166162299-C-T
• rs2278677
• NM_001366285.2:c.907+148G>A

Variant summary

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

The NM_001366285.2(TBXT):​c.907+148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 809,002 control chromosomes in the GnomAD database, including 11,928 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 0.18 (3332 hom., cov: 32)
  • Exomes 𝑓: 0.13 (8596 hom.)
• Consequence: TBXT NM_001366285.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.188
• Publications: 7 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: Orphanet, PanelApp Australia

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 (EAS) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

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.907+148G>A		intron	N/A	NP_001353214.1	J3KP65
	TBXT	NM_001366286.2		c.907+148G>A		intron	N/A	NP_001353215.1	J3KP65
	TBXT	NM_003181.4		c.904+148G>A		intron	N/A	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.907+148G>A		intron	N/A	ENSP00000355841.3	J3KP65
	TBXT	ENST00000366871.7	TSL:1	c.731-1333G>A		intron	N/A	ENSP00000355836.3	O15178-2
	TBXT	ENST00000296946.6	TSL:5	c.904+148G>A		intron	N/A	ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27172 AN: 152020 Hom.: 3335 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0977

Gnomad OTH AF: 0.152

GnomAD4 exome AF: 0.128 AC: 84080 AN: 656864 Hom.: 8596 AF XY: 0.125 AC XY: 42750 AN XY: 341430

African (AFR) AF: 0.323 AC: 5505 AN: 17052

American (AMR) AF: 0.111 AC: 3186 AN: 28602

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 1238 AN: 17102

East Asian (EAS) AF: 0.501 AC: 16320 AN: 32546

South Asian (SAS) AF: 0.102 AC: 5607 AN: 55074

European-Finnish (FIN) AF: 0.161 AC: 6530 AN: 40558

Middle Eastern (MID) AF: 0.120 AC: 304 AN: 2528

European-Non Finnish (NFE) AF: 0.0952 AC: 40965 AN: 430282

Other (OTH) AF: 0.134 AC: 4425 AN: 33120

GnomAD4 genome AF: 0.179 AC: 27188 AN: 152138 Hom.: 3332 Cov.: 32 AF XY: 0.182 AC XY: 13516 AN XY: 74404

African (AFR) AF: 0.318 AC: 13206 AN: 41474

American (AMR) AF: 0.114 AC: 1749 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3468

East Asian (EAS) AF: 0.498 AC: 2573 AN: 5164

South Asian (SAS) AF: 0.107 AC: 515 AN: 4830

European-Finnish (FIN) AF: 0.165 AC: 1746 AN: 10594

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0977 AC: 6640 AN: 67996

Other (OTH) AF: 0.154 AC: 326 AN: 2114

Alfa AF: 0.124 Hom.: 897

Bravo AF: 0.186

Asia WGS AF: 0.283 AC: 985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.59
PhyloP100		-0.19
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2278677;

hg19: chr6-166575787;