chr14-28767325-T-C

Variant summary

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

The NM_005249.5(FOXG1):ā€‹c.46T>Cā€‹(p.Ser16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 30)
Exomes š‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

FOXG1
NM_005249.5 missense

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.91
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=0.16131723).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXG1NM_005249.5 linkuse as main transcriptc.46T>C p.Ser16Pro 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.46T>C p.Ser16Pro missense_variant 1/1 NM_005249.5 ENSP00000339004 P1
FOXG1ENST00000706482.1 linkuse as main transcriptc.46T>C p.Ser16Pro missense_variant 2/2 ENSP00000516406 P1
LINC01551ENST00000675861.1 linkuse as main transcriptn.374+1312T>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1321498
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
657380
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Rett syndrome, congenital variant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 20, 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. 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. This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 16 of the FOXG1 protein (p.Ser16Pro). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Benign
-0.085
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.44
T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.45
N
LIST_S2
Benign
0.71
T
M_CAP
Pathogenic
0.32
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
0.62
N;N
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.18
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.026
D
Polyphen
0.0040
B
Vest4
0.12
MutPred
0.25
Gain of catalytic residue at S16 (P = 0.0198);
MVP
0.46
ClinPred
0.56
D
GERP RS
2.0
Varity_R
0.47
gMVP
0.77

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: rs1881773666; hg19: chr14-29236531; API