NM_005249.5:c.460delG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005249.5(FOXG1):c.460delG(p.Glu154ArgfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000158 in 1,268,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E154E) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000016 ( 0 hom. )
Consequence
FOXG1
NM_005249.5 frameshift
NM_005249.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.76
Publications
28 publications found
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 was made for transcript
Our verdict: Pathogenic. The variant received 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 226 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-28767732-CG-C is Pathogenic according to our data. Variant chr14-28767732-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 372563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_005249.5. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FOXG1 | TSL:6 MANE Select | c.460delG | p.Glu154ArgfsTer38 | frameshift | Exon 1 of 1 | ENSP00000339004.3 | P55316 | ||
| FOXG1 | c.460delG | p.Glu154ArgfsTer38 | frameshift | Exon 2 of 2 | ENSP00000516406.1 | P55316 | |||
| LINC01551 | n.374+1726delG | intron | N/A |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000765 AC: 1AN: 130702 AF XY: 0.0000140 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
130702
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000158 AC: 2AN: 1268510Hom.: 0 Cov.: 34 AF XY: 0.00000159 AC XY: 1AN XY: 628082 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
1268510
Hom.:
Cov.:
34
AF XY:
AC XY:
1
AN XY:
628082
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
29584
American (AMR)
AF:
AC:
0
AN:
35130
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
23834
East Asian (EAS)
AF:
AC:
0
AN:
33978
South Asian (SAS)
AF:
AC:
0
AN:
76688
European-Finnish (FIN)
AF:
AC:
1
AN:
30336
Middle Eastern (MID)
AF:
AC:
0
AN:
3768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
981818
Other (OTH)
AF:
AC:
0
AN:
53374
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.250
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Rett syndrome, congenital variant (3)
2
-
-
not provided (2)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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