rs1057516042
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_181486.4(TBX5):c.105del(p.Ser36AlafsTer30) 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 18 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-TG-T is Pathogenic according to our data. Variant chr12-114403793-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 369677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBX5 | NM_181486.4 | c.105del | p.Ser36AlafsTer30 | frameshift_variant | 2/9 | ENST00000405440.7 | |
TBX5 | NM_000192.3 | c.105del | p.Ser36AlafsTer30 | frameshift_variant | 2/9 | ||
TBX5 | XM_017019912.2 | c.153del | p.Ser52AlafsTer30 | frameshift_variant | 2/9 | ||
TBX5 | NM_080717.4 | c.-3-1874del | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBX5 | ENST00000405440.7 | c.105del | p.Ser36AlafsTer30 | 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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Holt-Oram syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 17, 2014 | This single nucleotide deletion is predicted to cause a frameshift resulting in a premature stop codon 30 amino acids downstream, and haploinsufficiency of TBX5. In-silico software (MutationTaster) predicts this variant to be disease-causing. This is a novel variant not present in population or disease databases. It segregated with disease in two additional family members. - |
Aortic valve disease 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | This sequence change creates a premature translational stop signal (p.Ser36Alafs*30) in the TBX5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBX5 are known to be pathogenic (PMID: 16183809, 16917909). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Holt-Oram syndrome (PMID: 26938784, 29755943). ClinVar contains an entry for this variant (Variation ID: 369677). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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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