22-19779418-C-T
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_080646.2(TBX1):c.*11C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,062 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0021 ( 2 hom. )
Consequence
TBX1
NM_080646.2 3_prime_UTR
NM_080646.2 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.11
Genes affected
TBX1 (HGNC:11592): (T-box transcription factor 1) 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 product shares 98% amino acid sequence identity with the mouse ortholog. DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS), a common congenital disorder characterized by neural-crest-related developmental defects, has been associated with deletions of chromosome 22q11.2, where this gene has been mapped. Studies using mouse models of DiGeorge syndrome suggest a major role for this gene in the molecular etiology of DGS/VCFS. Several alternatively spliced 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 Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 22-19779418-C-T is Benign according to our data. Variant chr22-19779418-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504975.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr22-19779418-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00121 (184/152230) while in subpopulation NFE AF= 0.00228 (155/68016). AF 95% confidence interval is 0.00199. There are 1 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 184 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TBX1 | NM_080646.2 | c.*11C>T | 3_prime_UTR_variant | 9/9 | NP_542377.1 | |||
| TBX1 | NM_005992.1 | c.1010-3495C>T | intron_variant | NP_005983.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TBX1 | ENST00000329705.11 | c.*11C>T | 3_prime_UTR_variant | 9/9 | 1 | ENSP00000331176.7 | ||||
| TBX1 | ENST00000359500.7 | c.1010-3495C>T | intron_variant | 1 | ENSP00000352483.3 |
Frequencies
GnomAD3 genomes 0.00121 AC: 184AN: 152112Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00131 AC: 330AN: 251156Hom.: 2 AF XY: 0.00132 AC XY: 179AN XY: 135836
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GnomAD4 exome AF: 0.00207 AC: 3025AN: 1461832Hom.: 2 Cov.: 33 AF XY: 0.00197 AC XY: 1435AN XY: 727222
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GnomAD4 genome 0.00121 AC: 184AN: 152230Hom.: 1 Cov.: 33 AF XY: 0.00116 AC XY: 86AN XY: 74420
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 27, 2016 | Variant classified as Uncertain Significance - Favor Benign. The c.*11C>T varian t in TBX1 has been reported in 1 individual with TOF and his presumably unaffect ed mother. The patient also carried variants in other genes associated with cong enital heart defects (Topf 2014). This variant has been identified in 0.2% (133/ 44688) of European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs72646973). Although it has been seen in the ge neral population, its frequency is not high enough to rule out a pathogenic role . In summary, while the clinical significance of the c.*11C>T variant is uncerta in, its frequency suggest that it is more likely to be benign. - |
not provided Benign:1
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | TBX1: BS1, BS2 - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at