rs878853149
Variant names:
Your query was ambiguous. Multiple possible variants found:
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
Genomes: not found (cov: 32)
Consequence
TCF4
NM_001083962.2 stop_gained
NM_001083962.2 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.95
Genes affected
TCF4 (HGNC:11634): (transcription factor 4) This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-55350388-G-A is Pathogenic according to our data. Variant chr18-55350388-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 235853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-55350388-G-A is described in Lovd as [Pathogenic]. Variant chr18-55350388-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pitt-Hopkins syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 25, 2018 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 06, 2024 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2022 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | TCF4: PVS1, PM2, PS2:Supporting, PS4:Supporting - |
Pitt-Hopkins syndrome;C2750451:Corneal dystrophy, Fuchs endothelial, 3 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Feb 08, 2022 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Jul 25, 2014 | - - |
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
Vest4
0.99, 0.99, 0.98, 0.98, 0.98, 0.98, 0.97, 0.99, 0.99
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