rs730880274
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005149.3(TBX19):βc.782delAβ(p.Asn261IlefsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005149.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBX19 | ENST00000367821.8 | c.782delA | p.Asn261IlefsTer46 | frameshift_variant | Exon 6 of 8 | 1 | NM_005149.3 | ENSP00000356795.3 | ||
TBX19 | ENST00000441464.1 | c.278delA | p.Asn93fs | frameshift_variant | Exon 3 of 5 | 2 | ENSP00000390731.1 | |||
TBX19 | ENST00000431969.5 | c.524-3680delA | intron_variant | Intron 4 of 5 | 5 | ENSP00000397540.1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251390Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135880
GnomAD4 exome AF: 0.0000985 AC: 144AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.000113 AC XY: 82AN XY: 727232
GnomAD4 genome AF: 0.000105 AC: 16AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:4
The c.782delA pathogenic variant in the TBX19 gene has been reported previously in association with isolated ACTH deficiency (Metherell et al., 2004). The c.782delA variant causes a frameshift starting with codon Asparagine 261, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 46 of the new reading frame, denoted p.Asn261IlefsX46. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.782delA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.782delA as apathogenic variant. -
TBX19: PVS1, PM3:Strong, PM2 -
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Congenital isolated adrenocorticotropic hormone deficiency Pathogenic:3
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Variant summary: TBX19 c.782delA (p.Asn261IlefsX46) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.4e-05 in 251390 control chromosomes. c.782delA has been reported in the literature in multiple individuals affected with Adrenocorticotropic Hormone Deficiency in the homozyous and compound heterozyous state (Metherell_2004, Vallette-Kasic_2005, Pulichino_2003). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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TBX19-related disorder Pathogenic:1
The TBX19 c.782delA variant is predicted to result in a frameshift and premature protein termination (p.Asn261Ilefs*46). This variant has been reported in patients with isolated ACTH deficiency (Pulichino et al. 2003. PubMed ID: 12651888; Jullien et al. 2020. PubMed ID: 33098107). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-168274298-CA-C). Frameshift variants in TBX19 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at