rs202193096
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_004608.4(TBX6):c.434C>T(p.Pro145Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
TBX6
NM_004608.4 missense
NM_004608.4 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 6.80
Genes affected
TBX6 (HGNC:11605): (T-box transcription factor 6) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Knockout studies in mice indicate that this gene is important for specification of paraxial mesoderm structures. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.755
PP5
Variant 16-30089130-G-A is Pathogenic according to our data. Variant chr16-30089130-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188056.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBX6 | NM_004608.4 | c.434C>T | p.Pro145Leu | missense_variant | 4/9 | ENST00000395224.7 | NP_004599.2 | |
TBX6 | XM_011545926.4 | c.434C>T | p.Pro145Leu | missense_variant | 4/9 | XP_011544228.1 | ||
TBX6 | XM_047434551.1 | c.434C>T | p.Pro145Leu | missense_variant | 3/8 | XP_047290507.1 | ||
TBX6 | XR_007064904.1 | n.557C>T | non_coding_transcript_exon_variant | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBX6 | ENST00000395224.7 | c.434C>T | p.Pro145Leu | missense_variant | 4/9 | 1 | NM_004608.4 | ENSP00000378650.2 | ||
TBX6 | ENST00000279386.6 | c.434C>T | p.Pro145Leu | missense_variant | 3/8 | 1 | ENSP00000279386.2 | |||
TBX6 | ENST00000553607.1 | c.434C>T | p.Pro145Leu | missense_variant | 3/5 | 1 | ENSP00000461223.1 | |||
TBX6 | ENST00000567664.5 | n.434C>T | non_coding_transcript_exon_variant | 3/7 | 5 | ENSP00000460425.1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000216 AC: 54AN: 250098Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135440
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GnomAD4 exome AF: 0.000105 AC: 153AN: 1461752Hom.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73AN XY: 727178
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GnomAD4 genome AF: 0.000105 AC: 16AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74488
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Scoliosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital | Aug 01, 2019 | This variant in trans with hypomorphic TBX6 allele may contribute to congenital scoliosis development - |
Spondylocostal dysostosis 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 22, 2015 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 145 of the TBX6 protein (p.Pro145Leu). This variant is present in population databases (rs202193096, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital scoliosis (PMID: 25564734, 31471994). ClinVar contains an entry for this variant (Variation ID: 188056). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBX6 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TBX6 function (PMID: 28054739, 31015262). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;L
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at