Genetic Variant NM_001366285.2:c.530G>T (chr6-166165782-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001366285.2(TBXT):c.530G>T(p.Gly177Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G177D) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TBXT
NM_001366285.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.58

Publications

0 publications found

Variant links:

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 Submitted by: Orphanet

TBXT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBXT	NM_001366285.2 link	c.530G>T	p.Gly177Val	missense_variant	Exon 3 of 8	ENST00000366876.7	NP_001353214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TBXT	ENST00000366876.7 link	c.530G>T	p.Gly177Val	missense_variant	Exon 3 of 8	1	NM_001366285.2	ENSP00000355841.3
TBXT	ENST00000366871.7 link	c.530G>T	p.Gly177Val	missense_variant	Exon 4 of 8	1		ENSP00000355836.3
TBXT	ENST00000296946.6 link	c.530G>T	p.Gly177Val	missense_variant	Exon 4 of 9	5		ENSP00000296946.2
TBXT	ENST00000461348.2 link	c.530G>T	p.Gly177Val	missense_variant	Exon 4 of 6	5		ENSP00000453512.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.74

D;.;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;D;T;D

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

5.6

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.1

D;D;D;D

REVEL

Uncertain

0.45

Sift

Benign

0.041

D;D;D;D

Sift4G

Benign

0.10

T;T;.;T

Vest4

0.51

ClinPred

0.95

GERP RS

4.1

Varity_R

0.84

gMVP

0.83

Mutation Taster

=20/80

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over