rs369050575
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2
The NM_001379200.1(TBX1):c.336_338delGAA(p.Lys112del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000142 in 1,526,856 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001379200.1 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBX1 | NM_001379200.1 | c.336_338delGAA | p.Lys112del | disruptive_inframe_deletion | Exon 1 of 7 | ENST00000649276.2 | NP_001366129.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBX1 | ENST00000649276.2 | c.336_338delGAA | p.Lys112del | disruptive_inframe_deletion | Exon 1 of 7 | NM_001379200.1 | ENSP00000497003.1 |
Frequencies
GnomAD3 genomes AF: 0.000333 AC: 50AN: 150306Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000398 AC: 79AN: 198560Hom.: 2 AF XY: 0.000290 AC XY: 32AN XY: 110292
GnomAD4 exome AF: 0.000121 AC: 167AN: 1376454Hom.: 1 AF XY: 0.0000949 AC XY: 65AN XY: 684920
GnomAD4 genome AF: 0.000332 AC: 50AN: 150402Hom.: 0 Cov.: 32 AF XY: 0.000327 AC XY: 24AN XY: 73430
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
This variant is associated with the following publications: (PMID: 28272434) -
TBX1: PM4, BS2 -
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not specified Benign:1
Variant summary: TBX1 c.309_311delGAA (p.Lys103del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0004 in 198560 control chromosomes, predominantly at a frequency of 0.65% within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in TBX1 causing TBX1-Related Disorders phenotype. The variant, c.309_311delGAA, has been reported in a cohort of Chinese individuals affected with (suspected) TBX1-Related Disorders with an allele frequency of 1.2%, including 1 homozygous patient (Xu_2017). Authors of this study also reported experimental evidence evaluating an impact on protein function, and demonstrated decreased protein levels together with decreased transcriptional activity in in vitro expression systems (Xu_2017), however neither decreased mRNA levels, nor increased protein degradation was found which could explain their findings, thus these data do not allow convincing conclusions about the variant effect. The following publication have been ascertained in the context of this evaluation (PMID: 28272434). ClinVar contains an entry for this variant (Variation ID: 455791). Based on the evidence outlined above, the variant was classified as likely benign. -
TBX1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
DiGeorge syndrome Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at