14-28767968-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_005249.5(FOXG1):​c.689G>T​(p.Arg230Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FOXG1
NM_005249.5 missense

Scores

17
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 9.87
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]
LINC01551 (HGNC:19828): (long intergenic non-protein coding RNA 1551)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a helix (size 13) in uniprot entity FOXG1_HUMAN there are 7 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 chr14-28767967-C-T is described in Lovd as [Pathogenic].
PP2
Missense variant in the FOXG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 90 curated pathogenic missense variants (we use a threshold of 10). The gene has 66 curated benign missense variants. Trascript score misZ: 3.7891 (above the threshold of 3.09). GenCC associations: The gene is linked to Rett syndrome, congenital variant, FOXG1 disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977
PP5
Variant 14-28767968-G-T is Pathogenic according to our data. Variant chr14-28767968-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288531.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXG1NM_005249.5 linkc.689G>T p.Arg230Leu missense_variant Exon 1 of 1 ENST00000313071.7 NP_005240.3 P55316

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXG1ENST00000313071.7 linkc.689G>T p.Arg230Leu missense_variant Exon 1 of 1 6 NM_005249.5 ENSP00000339004.3 P55316
FOXG1ENST00000706482.1 linkc.689G>T p.Arg230Leu missense_variant Exon 2 of 2 ENSP00000516406.1 P55316
LINC01551ENST00000675861.1 linkn.374+1955G>T intron_variant Intron 1 of 3

Frequencies

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

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:1
Mar 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 230 of the FOXG1 protein (p.Arg230Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Rett syndrome (PMID: 30214071; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 288531). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXG1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg230 amino acid residue in FOXG1. Other variant(s) that disrupt this residue have been observed in individuals with FOXG1-related conditions (PMID: 22129046; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1
Jul 01, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.4
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.82
Loss of MoRF binding (P = 6e-04);
MVP
0.99
ClinPred
1.0
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.97
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: rs786205007; hg19: chr14-29237174; API