14-28767528-GC-GCC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005249.5(FOXG1):c.256dupC(p.Gln86ProfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). The gene FOXG1 is included in the ClinGen Criteria Specification Registry.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000044 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
FOXG1
NM_005249.5 frameshift
NM_005249.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.607
Publications
10 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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new If you want to explore the variant's impact on the transcript NM_005249.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
ACMG classification
Specifications for FOXG1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 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 254 pathogenic variants in the truncated region.
PP5
Variant 14-28767528-G-GC is Pathogenic according to our data. Variant chr14-28767528-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 189613.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.256dupC | p.Gln86ProfsTer35 | frameshift | Exon 1 of 1 | ENSP00000339004.3 | P55316 | ||
| FOXG1 | c.256dupC | p.Gln86ProfsTer35 | frameshift | Exon 2 of 2 | ENSP00000516406.1 | P55316 | |||
| LINC01551 | n.374+1522dupC | intron | N/A |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 146708Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
0
AN:
146708
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000438 AC: 4AN: 913400Hom.: 0 Cov.: 16 AF XY: 0.00000232 AC XY: 1AN XY: 430174 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
4
AN:
913400
Hom.:
Cov.:
16
AF XY:
AC XY:
1
AN XY:
430174
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:
17750
American (AMR)
AF:
AC:
0
AN:
3900
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
8158
East Asian (EAS)
AF:
AC:
1
AN:
11468
South Asian (SAS)
AF:
AC:
0
AN:
17910
European-Finnish (FIN)
AF:
AC:
0
AN:
11280
Middle Eastern (MID)
AF:
AC:
0
AN:
2104
European-Non Finnish (NFE)
AF:
AC:
3
AN:
807976
Other (OTH)
AF:
AC:
0
AN:
32854
⚠️ 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: 0.225
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00 AC: 0AN: 146708Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 71344
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
146708
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
71344
African (AFR)
AF:
AC:
0
AN:
40700
American (AMR)
AF:
AC:
0
AN:
14746
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3388
East Asian (EAS)
AF:
AC:
0
AN:
5084
South Asian (SAS)
AF:
AC:
0
AN:
4778
European-Finnish (FIN)
AF:
AC:
0
AN:
8712
Middle Eastern (MID)
AF:
AC:
0
AN:
302
European-Non Finnish (NFE)
AF:
AC:
0
AN:
66078
Other (OTH)
AF:
AC:
0
AN:
2014
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
7
-
-
FOXG1 disorder (8)
3
-
-
not provided (3)
1
-
-
Abnormality of the nervous system (1)
1
-
-
FOXG1-related disorder (1)
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
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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