chr14-28767410-A-AC
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005249.5(FOXG1):c.136dup(p.Gln46ProfsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000236 in 1,269,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000024 ( 0 hom. )
Consequence
FOXG1
NM_005249.5 frameshift
NM_005249.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.127
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 248 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-28767410-A-AC is Pathogenic according to our data. Variant chr14-28767410-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 205496.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXG1 | NM_005249.5 | c.136dup | p.Gln46ProfsTer75 | frameshift_variant | 1/1 | ENST00000313071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXG1 | ENST00000313071.7 | c.136dup | p.Gln46ProfsTer75 | frameshift_variant | 1/1 | NM_005249.5 | P1 | ||
FOXG1 | ENST00000706482.1 | c.136dup | p.Gln46ProfsTer75 | frameshift_variant | 2/2 | P1 | |||
LINC01551 | ENST00000675861.1 | n.374+1402dup | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome AF: 0.00000236 AC: 3AN: 1269798Hom.: 0 Cov.: 31 AF XY: 0.00000159 AC XY: 1AN XY: 629736
GnomAD4 exome
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3
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1269798
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31
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1
AN XY:
629736
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GnomAD4 genome ? Cov.: 30
GnomAD4 genome
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Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2014 | The c.136dupC mutation in the FOXG1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The c.136dupC mutation causes a frameshift starting with codon Glutamine 46, changes this amino acid to a Proline residue and creates a premature Stop codon at position 75 of the new reading frame, denoted p.Gln46ProfsX75. This mutation is predicted to cause loss of normal protein function through protein truncation. The c.136dupC mutation was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.136dupC as a disease-causing mutation. The variant is found in FOXG1, panel(s). - |
Rett syndrome, congenital variant Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant classified as Pathogenic and reported on 01-31-2014 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at