NM_005249.5:c.765G>C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_005249.5(FOXG1):​c.765G>C​(p.Trp255Cys) 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 Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W255R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FOXG1
NM_005249.5 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P: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 17 ACMG points.

PS1
Transcript NM_005249.5 (FOXG1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 158601
PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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 chr14-28768042-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1704912.Status of the report is criteria_provided_single_submitter, 1 stars.
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, 0.988
PP5
Variant 14-28768044-G-C is Pathogenic according to our data. Variant chr14-28768044-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3024268.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXG1NM_005249.5 linkc.765G>C p.Trp255Cys 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.765G>C p.Trp255Cys missense_variant Exon 1 of 1 6 NM_005249.5 ENSP00000339004.3 P55316
FOXG1ENST00000706482.1 linkc.765G>C p.Trp255Cys missense_variant Exon 2 of 2 ENSP00000516406.1 P55316
LINC01551ENST00000675861.1 linkn.374+2031G>C intron_variant Intron 1 of 3

Frequencies

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

ClinVar

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

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:1
-
Molecular Genetics Lab, CHRU Brest
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
35
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Pathogenic
0.95
D
PROVEAN
Pathogenic
-12
D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.85
Gain of catalytic residue at N253 (P = 0.0037);
MVP
0.97
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-29237250; API