rs786205005
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_005249.5(FOXG1):c.577G>A(p.Ala193Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A193D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005249.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXG1 | NM_005249.5 | c.577G>A | p.Ala193Thr | missense_variant | 1/1 | ENST00000313071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXG1 | ENST00000313071.7 | c.577G>A | p.Ala193Thr | missense_variant | 1/1 | NM_005249.5 | P1 | ||
FOXG1 | ENST00000706482.1 | c.577G>A | p.Ala193Thr | missense_variant | 2/2 | P1 | |||
LINC01551 | ENST00000675861.1 | n.374+1843G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Rett syndrome, congenital variant Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 08, 2017 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (PMID:  22190898, 27029630, 24836831).  ClinVar contains an entry for this variant (Variation ID: 189616). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 193 of the FOXG1 protein (p.Ala193Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. - |
Pathogenic, no assertion criteria provided | curation | RettBASE | May 18, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.Ala193Thr in FOXG1 has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (Van der Aa N et. al., 2011). The p.Ala193Thr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic, but no details are available for independent assessment. The amino acid Ala at position 193 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Ala193Thr in FOXG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 20, 2018 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 05, 2016 | - - |
FOXG1 disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | May 30, 2024 | This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in at least 2 individuals with FOXG1 disorder, without confirmation of paternity and maternity (PM6_Strong). PMID: 22190898, PMID: 28661489 Has been observed in at least 5 individuals with phenotypes consistent with FOXG1 disorder (PS4). PMID:22190898 PMID:27029630 PMID:31199603 PMID:24766421 PMID:26344814 PMID:18571142 PMID:21441262 PMID:28661489 PMID:24836831 Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at