rs1555321294
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005249.5(FOXG1):c.500del(p.Glu167GlyfsTer25) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E167E) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
FOXG1
NM_005249.5 frameshift
NM_005249.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.50
Genes affected
FOXG1 (HGNC:3811): (forkhead box G1) This locus encodes a member of the fork-head transcription factor family. The encoded protein, which functions as a transcriptional repressor, is highly expressed in neural tissues during brain development. Mutations at this locus have been associated with Rett syndrome and a diverse spectrum of neurodevelopmental disorders defined as part of the FOXG1 syndrome. This gene is disregulated in many types of cancer and is the target of multiple microRNAs that regulate the proliferation of tumor cells. [provided by RefSeq, Jul 2020]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 210 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-28767778-GA-G is Pathogenic according to our data. Variant chr14-28767778-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 471469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXG1 | NM_005249.5 | c.500del | p.Glu167GlyfsTer25 | frameshift_variant | 1/1 | ENST00000313071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXG1 | ENST00000313071.7 | c.500del | p.Glu167GlyfsTer25 | frameshift_variant | 1/1 | NM_005249.5 | P1 | ||
FOXG1 | ENST00000706482.1 | c.500del | p.Glu167GlyfsTer25 | frameshift_variant | 2/2 | P1 | |||
LINC01551 | ENST00000675861.1 | n.374+1766del | intron_variant, non_coding_transcript_variant |
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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rett syndrome, congenital variant Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Mar 23, 2022 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 30, 2017 | For these reasons, this variant has been classified as Pathogenic. A different truncation downstream of this variant (p.Gly169Alafs*23) has been determined to be pathogenic (PMID: 25356899, Invitae). This suggests that deletion of this region of the FOXG1 protein is causative of disease. This variant has not been reported in the literature in individuals with a FOXG1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FOXG1 gene (p.Glu167Glyfs*25). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 323 amino acids of the FOXG1 protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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