rs35819705

Variant names:

• chr6-166158447-C-T
• rs35819705
• NM_001366285.2:c.1179G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001366285.2(TBXT):​c.1179G>A​(p.Ala393Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,613,956 control chromosomes in the GnomAD database, including 69,320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4910 hom., cov: 33)
  • Exomes 𝑓: 0.29 (64410 hom.)
• Consequence: TBXT NM_001366285.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.99
• Publications: 11 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 6-166158447-C-T is Benign according to our data. Variant chr6-166158447-C-T is described in ClinVar as Benign. ClinVar VariationId is 1241738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.307 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.1179G>A	p.Ala393Ala	synonymous	Exon 8 of 8	NP_001353214.1	J3KP65
	TBXT	NM_001366286.2		c.1179G>A	p.Ala393Ala	synonymous	Exon 9 of 9	NP_001353215.1	J3KP65
	TBXT	NM_003181.4		c.1176G>A	p.Ala392Ala	synonymous	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.1179G>A	p.Ala393Ala	synonymous	Exon 8 of 8	ENSP00000355841.3	J3KP65
	TBXT	ENST00000366871.7	TSL:1	c.1002G>A	p.Ala334Ala	synonymous	Exon 8 of 8	ENSP00000355836.3	O15178-2
	TBXT	ENST00000296946.6	TSL:5	c.1176G>A	p.Ala392Ala	synonymous	Exon 9 of 9	ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35320 AN: 152072 Hom.: 4908 Cov.: 33

Gnomad AFR AF: 0.0786

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.258

GnomAD2 exomes AF: 0.281 AC: 70599 AN: 251018 AF XY: 0.286

Gnomad AFR exome AF: 0.0745

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.293 AC: 428783 AN: 1461766 Hom.: 64410 Cov.: 71 AF XY: 0.294 AC XY: 214148 AN XY: 727194

African (AFR) AF: 0.0669 AC: 2239 AN: 33478

American (AMR) AF: 0.311 AC: 13898 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 8131 AN: 26126

East Asian (EAS) AF: 0.300 AC: 11922 AN: 39698

South Asian (SAS) AF: 0.313 AC: 26992 AN: 86250

European-Finnish (FIN) AF: 0.202 AC: 10752 AN: 53348

Middle Eastern (MID) AF: 0.270 AC: 1555 AN: 5768

European-Non Finnish (NFE) AF: 0.302 AC: 335536 AN: 1111988

Other (OTH) AF: 0.294 AC: 17758 AN: 60390

GnomAD4 genome AF: 0.232 AC: 35323 AN: 152190 Hom.: 4910 Cov.: 33 AF XY: 0.230 AC XY: 17148 AN XY: 74416

African (AFR) AF: 0.0783 AC: 3255 AN: 41560

American (AMR) AF: 0.312 AC: 4777 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1096 AN: 3462

East Asian (EAS) AF: 0.319 AC: 1646 AN: 5154

South Asian (SAS) AF: 0.319 AC: 1539 AN: 4822

European-Finnish (FIN) AF: 0.188 AC: 1992 AN: 10600

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20205 AN: 67986

Other (OTH) AF: 0.258 AC: 546 AN: 2114

Alfa AF: 0.266 Hom.: 2595

Bravo AF: 0.234

Asia WGS AF: 0.318 AC: 1106 AN: 3478

EpiCase AF: 0.313

EpiControl AF: 0.301

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
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.12
DANN	Benign	0.67
PhyloP100		-4.0
Mutation Taster		=98/2	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: rs35819705; hg19: chr6-166571935; COSMIC: COSV51616004;