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
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. - |
Pathogenic, no assertion criteria provided | curation | RettBASE | May 18, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 20, 2018 | - - |
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. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 05, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at