NM_005249.5:c.501G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005249.5(FOXG1):​c.501G>T​(p.Glu167Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.19882414).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXG1NM_005249.5 linkc.501G>T p.Glu167Asp 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.501G>T p.Glu167Asp missense_variant Exon 1 of 1 6 NM_005249.5 ENSP00000339004.3 P55316
FOXG1ENST00000706482.1 linkc.501G>T p.Glu167Asp missense_variant Exon 2 of 2 ENSP00000516406.1 P55316
LINC01551ENST00000675861.1 linkn.374+1767G>T intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000430
AC:
1
AN:
232292
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
127416
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000296
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1450144
Hom.:
0
Cov.:
36
AF XY:
0.00000139
AC XY:
1
AN XY:
721086
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000226
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Rett syndrome, congenital variant Uncertain:1
May 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 167 of the FOXG1 protein (p.Glu167Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. 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 not expected to disrupt FOXG1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Benign
0.29
T
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.35
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.58
T
M_CAP
Pathogenic
0.79
D
MetaRNN
Benign
0.20
T
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
0.27
N
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-0.30
N
REVEL
Benign
0.17
Sift
Benign
0.12
T
Sift4G
Benign
0.34
T
Polyphen
0.17
B
Vest4
0.099
MutPred
0.27
Gain of catalytic residue at K164 (P = 0.1123);
MVP
0.36
ClinPred
0.15
T
GERP RS
2.2
Varity_R
0.13
gMVP
0.49

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: rs773297334; hg19: chr14-29236986; API