chr17-61456554-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001321120.2(TBX4):c.64G>T(p.Gly22Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TBX4
NM_001321120.2 stop_gained
NM_001321120.2 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.03
Genes affected
TBX4 (HGNC:11603): (T-box transcription factor 4) 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 the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 50 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-61456554-G-T is Pathogenic according to our data. Variant chr17-61456554-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1341425.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBX4 | NM_001321120.2 | c.64G>T | p.Gly22Ter | stop_gained | 2/9 | ENST00000644296.1 | |
LOC124904042 | XR_007065872.1 | n.2149C>A | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBX4 | ENST00000644296.1 | c.64G>T | p.Gly22Ter | stop_gained | 2/9 | NM_001321120.2 | A1 | ||
TBX4 | ENST00000240335.1 | c.64G>T | p.Gly22Ter | stop_gained | 1/8 | 1 | P4 | ||
TBX4 | ENST00000642491.1 | c.64G>T | p.Gly22Ter | stop_gained | 1/8 | A1 | |||
TBX4 | ENST00000589003.5 | c.-125-70G>T | intron_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1399198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 690512
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1399198
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
690512
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 Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 18, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1341425). This premature translational stop signal has been observed in individual(s) with pulmonary arterial hypertension (PMID: 30578397). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly22*) in the TBX4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBX4 are known to be pathogenic (PMID: 15106123, 31151956, 31761294, 31965066, 32079640). - |
Pulmonary hypertension, primary, 1 Other:1
not provided, no classification provided | literature only | Wendy Chung Laboratory, Columbia University Medical Center | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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
Publications
No publications associated with this variant yet.