rs28730763
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1
The NM_181486.4(TBX5):c.309C>T(p.Leu103Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00742 in 1,614,098 control chromosomes in the GnomAD database, including 794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.040 ( 402 hom., cov: 32)
Exomes 𝑓: 0.0041 ( 392 hom. )
Consequence
TBX5
NM_181486.4 synonymous
NM_181486.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.153
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
Variant 12-114399566-G-A is Benign according to our data. Variant chr12-114399566-G-A is described in ClinVar as [Benign]. Clinvar id is 213815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114399566-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.153 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBX5 | NM_181486.4 | c.309C>T | p.Leu103Leu | synonymous_variant | 4/9 | ENST00000405440.7 | NP_852259.1 | |
TBX5 | NM_000192.3 | c.309C>T | p.Leu103Leu | synonymous_variant | 4/9 | NP_000183.2 | ||
TBX5 | NM_080717.4 | c.159C>T | p.Leu53Leu | synonymous_variant | 3/8 | NP_542448.1 | ||
TBX5 | XM_017019912.2 | c.357C>T | p.Leu119Leu | synonymous_variant | 4/9 | XP_016875401.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBX5 | ENST00000405440.7 | c.309C>T | p.Leu103Leu | synonymous_variant | 4/9 | 1 | NM_181486.4 | ENSP00000384152.3 |
Frequencies
GnomAD3 genomes AF: 0.0396 AC: 6018AN: 152090Hom.: 397 Cov.: 32
GnomAD3 genomes
AF:
AC:
6018
AN:
152090
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0105 AC: 2644AN: 251494Hom.: 167 AF XY: 0.00731 AC XY: 994AN XY: 135922
GnomAD3 exomes
AF:
AC:
2644
AN:
251494
Hom.:
AF XY:
AC XY:
994
AN XY:
135922
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00406 AC: 5936AN: 1461890Hom.: 392 Cov.: 33 AF XY: 0.00345 AC XY: 2510AN XY: 727248
GnomAD4 exome
AF:
AC:
5936
AN:
1461890
Hom.:
Cov.:
33
AF XY:
AC XY:
2510
AN XY:
727248
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0397 AC: 6043AN: 152208Hom.: 402 Cov.: 32 AF XY: 0.0386 AC XY: 2873AN XY: 74442
GnomAD4 genome
AF:
AC:
6043
AN:
152208
Hom.:
Cov.:
32
AF XY:
AC XY:
2873
AN XY:
74442
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
37
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2016 | Variant summary: The TBX5 c.309C>T (p.Leu103Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. This variant was found in 1592/121410 control chromosomes (111 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1429258 (1487/10404). This frequency significantly exceeds the estimated maximal expected allele frequency of a pathogenic TBX5 variant (0.0000013), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in multiple affected individuals as a polymorphism. Some patient also carried a pathogenic variant, further supporting the benign classification of this variant. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Holt-Oram syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Aortic valve disease 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2015 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at