rs3816300

Positions:

• chr6-166158517-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001366285.2(TBXT):​c.1109A>G​(p.Asn370Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,606,472 control chromosomes in the GnomAD database, including 15,123 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (2121 hom., cov: 33)
  • Exomes 𝑓: 0.11 (13002 hom.)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.148

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1012185E-4).
• BP6: Variant 6-166158517-T-C is Benign according to our data. Variant chr6-166158517-T-C is described in ClinVar as [Benign]. Clinvar id is 3059077.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBXT	NM_001366285.2	c.1109A>G	p.Asn370Ser	missense_variant	8/8	ENST00000366876.7	NP_001353214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBXT	ENST00000366876.7	c.1109A>G	p.Asn370Ser	missense_variant	8/8	1	NM_001366285.2	ENSP00000355841.3
TBXT	ENST00000366871.7	c.932A>G	p.Asn311Ser	missense_variant	8/8	1		ENSP00000355836.3
TBXT	ENST00000296946.6	c.1106A>G	p.Asn369Ser	missense_variant	9/9	5		ENSP00000296946.2

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22240 AN: 152058 Hom.: 2119 Cov.: 33

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0970

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.142 AC: 34849 AN: 244648 Hom.: 3957 AF XY: 0.137 AC XY: 18198 AN XY: 132900

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.0779

Gnomad EAS exome AF: 0.518

Gnomad SAS exome AF: 0.0959

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.0967

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.112 AC: 163149 AN: 1454296 Hom.: 13002 Cov.: 35 AF XY: 0.111 AC XY: 80164 AN XY: 721938

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.0752

Gnomad4 EAS exome AF: 0.509

Gnomad4 SAS exome AF: 0.0972

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.0940

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.146 AC: 22260 AN: 152176 Hom.: 2121 Cov.: 33 AF XY: 0.150 AC XY: 11194 AN XY: 74390

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.0970

Gnomad4 OTH AF: 0.138

Alfa AF: 0.102 Hom.: 1237

Bravo AF: 0.150

TwinsUK AF: 0.0917 AC: 340

ALSPAC AF: 0.0939 AC: 362

ESP6500AA AF: 0.202 AC: 890

ESP6500EA AF: 0.0937 AC: 805

ExAC AF: 0.141 AC: 17032

Asia WGS AF: 0.283 AC: 984 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TBXT-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.081
DANN	Benign	0.23
DEOGEN2	Benign	0.060	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.72	T;T;T
MetaRNN	Benign	0.00011	T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.96	T;T;T
Sift4G	Benign	0.83	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.023
MPC		0.13
ClinPred		0.00082	T
GERP RS		-6.6
Varity_R		0.026
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs3816300; hg19: chr6-166572005; COSMIC: COSV51620082;