12-114403793-T-TG
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_181486.4(TBX5):c.105_106insC(p.Ser36GlnfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
TBX5
NM_181486.4 frameshift
NM_181486.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.83
Genes affected
TBX5 (HGNC:11604): (T-box transcription factor 5) 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. This gene is closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-114403793-T-TG is Pathogenic according to our data. Variant chr12-114403793-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 870089.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBX5 | NM_181486.4 | c.105_106insC | p.Ser36GlnfsTer25 | frameshift_variant | 2/9 | ENST00000405440.7 | |
TBX5 | NM_000192.3 | c.105_106insC | p.Ser36GlnfsTer25 | frameshift_variant | 2/9 | ||
TBX5 | XM_017019912.2 | c.153_154insC | p.Ser52GlnfsTer25 | frameshift_variant | 2/9 | ||
TBX5 | NM_080717.4 | c.-3-1874_-3-1873insC | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBX5 | ENST00000405440.7 | c.105_106insC | p.Ser36GlnfsTer25 | frameshift_variant | 2/9 | 1 | NM_181486.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Holt-Oram syndrome;C4021133:Left ventricular noncompaction cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Feb 09, 2018 | TBX5 Ser36Thrfs*25 has not been previously reported and is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a patient with Holt-Oram Syndrome, the patient initially presented with findings of left ventricular non-compaction and also has brachydactyly and pectus deformity associated to the condition (Ross et al., 2018). TBX5 variants have only ever been associated to Holt-Oram syndrome furthermore, TBX5 loss of function variants are an established mechanism of disease and the variant is very rare in the general population, consequently we classify TBX5 Ser36Thrfs*25 as 'pathogenic'. - |
Computational scores
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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