rs147405081
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_181486.4(TBX5):c.787G>A(p.Val263Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000882 in 1,614,004 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_181486.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBX5 | NM_181486.4 | c.787G>A | p.Val263Met | missense_variant | Exon 8 of 9 | ENST00000405440.7 | NP_852259.1 | |
TBX5 | NM_000192.3 | c.787G>A | p.Val263Met | missense_variant | Exon 8 of 9 | NP_000183.2 | ||
TBX5 | NM_080717.4 | c.637G>A | p.Val213Met | missense_variant | Exon 7 of 8 | NP_542448.1 | ||
TBX5 | XM_017019912.2 | c.835G>A | p.Val279Met | missense_variant | Exon 8 of 9 | XP_016875401.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBX5 | ENST00000405440.7 | c.787G>A | p.Val263Met | missense_variant | Exon 8 of 9 | 1 | NM_181486.4 | ENSP00000384152.3 | ||
TBX5 | ENST00000310346.8 | c.787G>A | p.Val263Met | missense_variant | Exon 8 of 9 | 1 | ENSP00000309913.4 | |||
TBX5 | ENST00000349716.9 | c.637G>A | p.Val213Met | missense_variant | Exon 7 of 8 | 1 | ENSP00000337723.5 | |||
TBX5 | ENST00000526441.1 | c.787G>A | p.Val263Met | missense_variant | Exon 7 of 7 | 1 | ENSP00000433292.1 |
Frequencies
GnomAD3 genomes AF: 0.00389 AC: 591AN: 152006Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00122 AC: 307AN: 251214Hom.: 0 AF XY: 0.000987 AC XY: 134AN XY: 135790
GnomAD4 exome AF: 0.000565 AC: 826AN: 1461880Hom.: 6 Cov.: 32 AF XY: 0.000507 AC XY: 369AN XY: 727238
GnomAD4 genome AF: 0.00392 AC: 597AN: 152124Hom.: 4 Cov.: 32 AF XY: 0.00405 AC XY: 301AN XY: 74358
ClinVar
Submissions by phenotype
not specified Benign:2
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Variant summary: The TBX5 c.787G>A (p.Val263Met) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Though a recent functional study demonstrated that the variant of interest could disrupts the TBX5-NuRD interaction (Waldron 2016), another study provided evidence that TBX5 activity may be extensively regulated through alternative splicing where the variant of interest would not affect isoforms lacking exon 9 (Yamak 2015). This variant was found in 403/276910 control chromosomes (with 1 homozygous occurrence), predominantly observed in the African subpopulation at a frequency of 0.012288 (295/24008). This frequency is about 2809 times the estimated maximal expected allele frequency of a pathogenic TBX5 variant (0.0000044), strong evidence that this is a benign polymorphism. The variant was reported in the literature in affected individuals, however without strong evidence for causality (Faria 2008, Bonachea 2014), i.e. no clear co-segregation could be demonstrated. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -
Holt-Oram syndrome Benign:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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not provided Benign:2
This variant is associated with the following publications: (PMID: 18706711, 25260786) -
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Aortic valve disease 2 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as 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