14-28767530-C-G

Variant summary

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

The NM_005249.5(FOXG1):ā€‹c.251C>Gā€‹(p.Pro84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 147,192 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 (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P84H) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000014 ( 0 hom., cov: 32)

Consequence

FOXG1
NM_005249.5 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.467
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.08721593).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXG1NM_005249.5 linkuse as main transcriptc.251C>G p.Pro84Arg missense_variant 1/1 ENST00000313071.7 NP_005240.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXG1ENST00000313071.7 linkuse as main transcriptc.251C>G p.Pro84Arg missense_variant 1/1 NM_005249.5 ENSP00000339004 P1
FOXG1ENST00000706482.1 linkuse as main transcriptc.251C>G p.Pro84Arg missense_variant 2/2 ENSP00000516406 P1
LINC01551ENST00000675861.1 linkuse as main transcriptn.374+1517C>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000136
AC:
2
AN:
147192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000245
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000675
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
17
GnomAD4 genome
AF:
0.0000136
AC:
2
AN:
147192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
71600
show subpopulations
Gnomad4 AFR
AF:
0.0000245
Gnomad4 AMR
AF:
0.0000675
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 08, 2015- -
Rett syndrome, congenital variant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 16, 2023In 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. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 84 of the FOXG1 protein (p.Pro84Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 281382). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.59
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.30
T
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.49
T
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.087
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
1.0
N;N
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
0.060
N
REVEL
Benign
0.022
Sift
Uncertain
0.0070
D
Sift4G
Benign
0.41
T
Polyphen
0.028
B
Vest4
0.12
MutPred
0.28
Gain of catalytic residue at P79 (P = 0.0047);
MVP
0.19
ClinPred
0.20
T
GERP RS
2.0
Varity_R
0.10
gMVP
0.19

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: rs866815665; hg19: chr14-29236736; API