rs878853149
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001083962.2(TCF4):c.520C>T(p.Arg174*) 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001083962.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Pitt-Hopkins syndrome Pathogenic:2
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
This sequence change creates a premature translational stop signal (p.Arg174*) in the TCF4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCF4 are known to be pathogenic (PMID: 18728071, 22045651). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pitt-Hopkins syndrome (PMID: 26993267). ClinVar contains an entry for this variant (Variation ID: 235853). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
TCF4: PVS1, PM2, PS2:Supporting, PS4:Supporting -
Nonsense 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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28807867, 22045651, 31278258, 30830316, 26993267, 25167861, 33084218, 31785789) -
Pitt-Hopkins syndrome;C2750451:Corneal dystrophy, Fuchs endothelial, 3 Pathogenic:1
This variant has been reported in the literature in 7 individuals, including as a de novo variants in at least 3 individuals (Selected publications: Redin 2014 PMID: 25167861; Trump 2016 PMID: 26993267; Turner 2019 PMID: 31785789). This variant is not present in large control databases but is present in ClinVar, with multiple labs classifying it as pathogenic (Variation ID: 235853). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense mediated mRNA decay. Loss of function variants are a known mechanism of disease for this gene (Bedeschi 2017 PMID: 28807867). In summary, this variant is classified as pathogenic. -
Intellectual disability Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at