rs144434028
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_005249.5(FOXG1):c.1323C>T(p.Ser441=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00037 ( 1 hom. )
Consequence
FOXG1
NM_005249.5 synonymous
NM_005249.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.659
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 Benign. Variant got -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
?
Variant 14-28768602-C-T is Benign according to our data. Variant chr14-28768602-C-T is described in ClinVar as [Benign]. Clinvar id is 137392.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-28768602-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=0.659 with no splicing effect.
BS2
?
High AC in GnomAd at 35 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXG1 | NM_005249.5 | c.1323C>T | p.Ser441= | synonymous_variant | 1/1 | ENST00000313071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXG1 | ENST00000313071.7 | c.1323C>T | p.Ser441= | synonymous_variant | 1/1 | NM_005249.5 | P1 | ||
FOXG1 | ENST00000706482.1 | c.1323C>T | p.Ser441= | synonymous_variant | 2/2 | P1 | |||
LINC01551 | ENST00000675861.1 | n.374+2589C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000263 AC: 66AN: 251402Hom.: 1 AF XY: 0.000280 AC XY: 38AN XY: 135900
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GnomAD4 exome AF: 0.000371 AC: 543AN: 1461884Hom.: 1 Cov.: 34 AF XY: 0.000358 AC XY: 260AN XY: 727244
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GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74336
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 28, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | FOXG1: BP4, BP7 - |
Rett syndrome, congenital variant Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Nov 03, 2017 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 28, 2017 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2016 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
FOXG1 disorder Benign:1
Benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Feb 18, 2022 | The p.Ser441= variant in FOXG1 has an allele frequency of 0.049% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Ser441= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1). - |
Computational scores
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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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