rs786205008

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_005249.5(FOXG1):​c.700T>C​(p.Ser234Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S234F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FOXG1
NM_005249.5 missense

Scores

11
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.23
Variant links:
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 19 ACMG points.

PM1
In a DNA_binding_region Fork-head (size 94) in uniprot entity FOXG1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_005249.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-28767980-C-T is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FOXG1. . Trascript score misZ 3.7891 (greater than threshold 3.09). GenCC has associacion of gene with Rett syndrome, congenital variant, FOXG1 disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977
PP5
Variant 14-28767979-T-C is Pathogenic according to our data. Variant chr14-28767979-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-28767979-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXG1NM_005249.5 linkuse as main transcriptc.700T>C p.Ser234Pro missense_variant 1/1 ENST00000313071.7 NP_005240.3 P55316

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXG1ENST00000313071.7 linkuse as main transcriptc.700T>C p.Ser234Pro missense_variant 1/16 NM_005249.5 ENSP00000339004.3 P55316
FOXG1ENST00000706482.1 linkuse as main transcriptc.700T>C p.Ser234Pro missense_variant 2/2 ENSP00000516406.1 P55316
LINC01551ENST00000675861.1 linkuse as main transcriptn.374+1966T>C intron_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:2
Pathogenic, no assertion criteria providedcurationRettBASESep 26, 2011- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 20, 2018- -
FOXG1 disorder Pathogenic:1
Likely pathogenic, criteria provided, single submittercurationCentre for Population Genomics, CPGMay 24, 2024This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in an individual with FOXG1 disorder without confirmation of paternity and maternity (PM6, PMID: 21441262). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
1.0
D
Eigen
Pathogenic
0.77
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.4
H
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-4.1
D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.016
D
Sift4G
Uncertain
0.037
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.81
Gain of catalytic residue at N232 (P = 0);
MVP
0.99
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.99
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786205008; hg19: chr14-29237185; COSMIC: COSV57395902; COSMIC: COSV57395902; API