NM_014444.5:c.579dupT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014444.5(TUBGCP4):c.579dupT(p.Gly194TrpfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_014444.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000124 AC: 31AN: 249472Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135348
GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000701 AC XY: 51AN XY: 727246
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74362
ClinVar
Submissions by phenotype
Microcephaly and chorioretinopathy 3 Pathogenic:4
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Variant summary: TUBGCP4 c.579dupT (p.Gly194TrpfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00012 in 249472 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TUBGCP4 causing Microcephaly And Chorioretinopathy 3, allowing no conclusion about variant significance. c.579dupT has been reported in the literature in two compound heterozygous individuals in a family affected with Microcephaly And Chorioretinopathy 3 (Scheidecker_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25817018). ClinVar contains an entry for this variant (Variation ID: 190124). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Gly194Trpfs*8) in the TUBGCP4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TUBGCP4 are known to be pathogenic (PMID: 25817018). This variant is present in population databases (rs765297510, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with clinical features of microcephaly and chorioretinal dysplasia (PMID: 25817018). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190124). For these reasons, this variant has been classified as Pathogenic. -
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34313030, 25817018) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at