rs2305089

Variant names:

• chr6-166165782-C-T
• rs2305089
• NM_001366285.2:c.530G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-166165782-C-T
• chr6-166165782-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366285.2(TBXT):​c.530G>A​(p.Gly177Asp) variant causes a missense change. The variant allele was found at a frequency of 0.489 in 1,613,758 control chromosomes in the GnomAD database, including 196,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14845 hom., cov: 32)
  • Exomes 𝑓: 0.49 (181610 hom.)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.58
• Publications: 67 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.0517578E-4).
• BP6: Variant 6-166165782-C-T is Benign according to our data. Variant chr6-166165782-C-T is described in ClinVar as Benign. ClinVar VariationId is 1242832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.505 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.530G>A	p.Gly177Asp	missense	Exon 3 of 8	NP_001353214.1	J3KP65
	TBXT	NM_001366286.2		c.530G>A	p.Gly177Asp	missense	Exon 4 of 9	NP_001353215.1	J3KP65
	TBXT	NM_003181.4		c.530G>A	p.Gly177Asp	missense	Exon 4 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.530G>A	p.Gly177Asp	missense	Exon 3 of 8	ENSP00000355841.3	J3KP65
	TBXT	ENST00000366871.7	TSL:1	c.530G>A	p.Gly177Asp	missense	Exon 4 of 8	ENSP00000355836.3	O15178-2
	TBXT	ENST00000296946.6	TSL:5	c.530G>A	p.Gly177Asp	missense	Exon 4 of 9	ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65060 AN: 151868 Hom.: 14833 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.478 AC: 120199 AN: 251484 AF XY: 0.483

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.541

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.338

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.495 AC: 723283 AN: 1461772 Hom.: 181610 Cov.: 54 AF XY: 0.495 AC XY: 360297 AN XY: 727196

African (AFR) AF: 0.250 AC: 8374 AN: 33478

American (AMR) AF: 0.533 AC: 23841 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 14652 AN: 26134

East Asian (EAS) AF: 0.322 AC: 12768 AN: 39698

South Asian (SAS) AF: 0.513 AC: 44287 AN: 86256

European-Finnish (FIN) AF: 0.395 AC: 21069 AN: 53406

Middle Eastern (MID) AF: 0.492 AC: 2834 AN: 5766

European-Non Finnish (NFE) AF: 0.509 AC: 565839 AN: 1111920

Other (OTH) AF: 0.490 AC: 29619 AN: 60394

GnomAD4 genome AF: 0.428 AC: 65105 AN: 151986 Hom.: 14845 Cov.: 32 AF XY: 0.424 AC XY: 31536 AN XY: 74308

African (AFR) AF: 0.266 AC: 11010 AN: 41450

American (AMR) AF: 0.505 AC: 7719 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1948 AN: 3470

East Asian (EAS) AF: 0.347 AC: 1791 AN: 5162

South Asian (SAS) AF: 0.513 AC: 2468 AN: 4814

European-Finnish (FIN) AF: 0.377 AC: 3975 AN: 10552

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34647 AN: 67950

Other (OTH) AF: 0.478 AC: 1006 AN: 2104

Alfa AF: 0.485 Hom.: 56524

Bravo AF: 0.431

TwinsUK AF: 0.505 AC: 1874

ALSPAC AF: 0.510 AC: 1965

ESP6500AA AF: 0.264 AC: 1164

ESP6500EA AF: 0.512 AC: 4407

ExAC AF: 0.474 AC: 57595

Asia WGS AF: 0.468 AC: 1627 AN: 3478

EpiCase AF: 0.525

EpiControl AF: 0.519

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Microcephaly-thin corpus callosum-intellectual disability syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.00031	T
MetaSVM	Benign	-0.82	T
PhyloP100		5.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.053	T
Polyphen		0.0060	B
Vest4		0.24
MPC		1.4
ClinPred		0.046	T
GERP RS		4.1
Varity_R		0.71
gMVP		0.78
Mutation Taster		=15/85	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: rs2305089; hg19: chr6-166579270; COSMIC: COSV51618064;