rs1057519050
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate
The NM_181486.4(TBX5):c.404T>G(p.Leu135Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
TBX5
NM_181486.4 missense
NM_181486.4 missense
Scores
9
7
1
Clinical Significance
Conservation
PhyloP100: 7.49
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_181486.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.921
PP5
?
Variant 12-114398679-A-C is Pathogenic according to our data. Variant chr12-114398679-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375289.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBX5 | NM_181486.4 | c.404T>G | p.Leu135Arg | missense_variant | 5/9 | ENST00000405440.7 | |
TBX5 | NM_000192.3 | c.404T>G | p.Leu135Arg | missense_variant | 5/9 | ||
TBX5 | NM_080717.4 | c.254T>G | p.Leu85Arg | missense_variant | 4/8 | ||
TBX5 | XM_017019912.2 | c.452T>G | p.Leu151Arg | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBX5 | ENST00000405440.7 | c.404T>G | p.Leu135Arg | missense_variant | 5/9 | 1 | NM_181486.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial atrioventricular septal defect Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Human Genetics and Genome Research Institute, National Research Centre | Jun 01, 2016 | Genomic DNA was extracted and followed by the Sanger sequencing and bioinformatics analysis. Analysis included computational predictions by MutationTaster2, Swiss-PdbViewer, The Ensembl Variant Effect Predictor, Protein Homology/analogY Recognition Engine V 2.0 (Phyre 2), DNA Baser v4.7.0.0, SNPnexus, Lasergene 6.0, NNSPLICE 0.9, and RegRNA 1.0. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0, 0.73
.;D;D;P
Vest4
MutPred
0.66
.;Gain of disorder (P = 0.0123);Gain of disorder (P = 0.0123);Gain of disorder (P = 0.0123);
MVP
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
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