rs267606826
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005249.5(FOXG1):c.624C>A(p.Tyr208*) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y208Y) has been classified as Likely benign.
Frequency
Consequence
NM_005249.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FOXG1 | ENST00000313071.7 | c.624C>A | p.Tyr208* | stop_gained | Exon 1 of 1 | 6 | NM_005249.5 | ENSP00000339004.3 | ||
FOXG1 | ENST00000706482.1 | c.624C>A | p.Tyr208* | stop_gained | Exon 2 of 2 | ENSP00000516406.1 | ||||
LINC01551 | ENST00000675861.1 | n.374+1890C>A | intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Rett syndrome, congenital variant Pathogenic:3
This sequence change results in a premature translational stop signal in the FOXG1 gene (p.Tyr208*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 282 amino acids of the FOXG1 protein. This variant is not present in population databases (ExAC no frequency). This nonsense change has been observed in individual(s) with clinical features of Rett syndrome (PMID: 28661489, 19578037). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 453289). For these reasons, this variant has been classified as Pathogenic. -
This terminating amino acid change (p.Y208X) has been reported in at least one affected individual (PMID 19578037). -
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Abnormal optic nerve morphology;C0038273:Stereotypic movement disorder;C0038379:Strabismus;C0557874:Global developmental delay;C1853743:Axial hypotonia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at