14-28767410-AC-ACC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005249.5(FOXG1):c.136dupC(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 (★). Synonymous variant affecting the same amino acid position (i.e. Q46Q) has been classified as Likely benign.
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
Publications
2 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 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 277 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 VariationId is 205496.Status of the report is criteria_provided_single_submitter, 1 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.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FOXG1 | NM_005249.5 | MANE Select | c.136dupC | p.Gln46ProfsTer75 | frameshift | Exon 1 of 1 | NP_005240.3 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FOXG1 | ENST00000313071.7 | TSL:6 MANE Select | c.136dupC | p.Gln46ProfsTer75 | frameshift | Exon 1 of 1 | ENSP00000339004.3 | ||
| FOXG1 | ENST00000706482.1 | c.136dupC | p.Gln46ProfsTer75 | frameshift | Exon 2 of 2 | ENSP00000516406.1 | |||
| LINC01551 | ENST00000675861.1 | n.374+1402dupC | intron | N/A |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
30
GnomAD4 exome AF: 0.00000236 AC: 3AN: 1269798Hom.: 0 Cov.: 31 AF XY: 0.00000159 AC XY: 1AN XY: 629736 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
3
AN:
1269798
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
629736
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
1
AN:
26114
American (AMR)
AF:
AC:
0
AN:
32044
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19724
East Asian (EAS)
AF:
AC:
0
AN:
26226
South Asian (SAS)
AF:
AC:
0
AN:
74814
European-Finnish (FIN)
AF:
AC:
1
AN:
42980
Middle Eastern (MID)
AF:
AC:
0
AN:
4094
European-Non Finnish (NFE)
AF:
AC:
0
AN:
995466
Other (OTH)
AF:
AC:
1
AN:
48336
⚠️ 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
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
30
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
not provided (1)
-
-
-
Rett syndrome, congenital variant (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
Publications
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