rs1555926209
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378418.1(TCF20):c.2224C>T(p.Arg742Ter) 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
TCF20
NM_001378418.1 stop_gained
NM_001378418.1 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 1.95
Genes affected
TCF20 (HGNC:11631): (transcription factor 20) This gene encodes a transcription factor that recognizes the platelet-derived growth factor-responsive element in the matrix metalloproteinase 3 promoter. The encoded protein is thought to be a transcriptional coactivator, enhancing the activity of transcription factors such as JUN and SP1. Mutations in this gene are associated with autism spectrum disorders. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]
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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 22-42213082-G-A is Pathogenic according to our data. Variant chr22-42213082-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 521787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-42213082-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TCF20 | NM_001378418.1 | c.2224C>T | p.Arg742Ter | stop_gained | 2/6 | ENST00000677622.1 | NP_001365347.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TCF20 | ENST00000677622.1 | c.2224C>T | p.Arg742Ter | stop_gained | 2/6 | NM_001378418.1 | ENSP00000503828 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurodevelopmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Neurodevelopmental abnormality Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2018 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2017 | - - |
Developmental delay with variable intellectual impairment and behavioral abnormalities Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 20, 2019 | - - |
not provided Pathogenic:1
Pathogenic, flagged submission | clinical testing | GeneDx | Nov 14, 2018 | The R742X variant in the TCF20 gene has been observed in internal GeneDx whole exome sequencing data in association with intellectual disability, global developmental delay, autism spectrum disorder, neurologic abnormalities, and dysmorphic features. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R742X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, we interpret R742X as a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
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