6-166158517-T-C

Position:

• 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). Synonymous variant affecting the same amino acid position (i.e. N370N) has been classified as Likely benign.

• 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	UniProt
TBXT	NM_001366285.2	c.1109A>G	p.Asn370Ser	missense_variant	8/8	ENST00000366876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXT	ENST00000366876.7	c.1109A>G	p.Asn370Ser	missense_variant	8/8	1	NM_001366285.2	P4
TBXT	ENST00000366871.7	c.932A>G	p.Asn311Ser	missense_variant	8/8	1
TBXT	ENST00000296946.6	c.1106A>G	p.Asn369Ser	missense_variant	9/9	5		A1

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
MutationTaster	Benign	0.83	P;P
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;