chr14-28767481-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005249.5(FOXG1):c.202C>T(p.Pro68Ser) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P68P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.707

Publications

2 publications found

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]

FOXG1 links:

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

LINC01551 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15093389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3	P55316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXG1	ENST00000313071.7 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 2 of 2			ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1 link	n.374+1468C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

73638

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1004054

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

485576

African (AFR)

AF:

0.00

AC:

AN:

20322

American (AMR)

AF:

0.00

AC:

AN:

18730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13324

East Asian (EAS)

AF:

0.00

AC:

AN:

13454

South Asian (SAS)

AF:

0.00

AC:

AN:

38048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2414

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

845782

Other (OTH)

AF:

0.00

AC:

AN:

35758

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 31, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2014

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro68Ser (CCG>TCG): c.202 C>T in exon 1 of the FOXG1 gene (NM_005249.3). A variant of unknown significance has been identified in the FOXG1 gene. The P68S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 2,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P68S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and it does not occur within the forkhead binding domain where all previously reported missense mutations in FOXG1 have been identified. Additionally, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in MICROCEPHALY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

0.71

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.030

REVEL

Benign

0.043

Sift

Uncertain

0.025

Sift4G

Benign

0.88

Polyphen

0.34

Vest4

0.22

MutPred

0.37

Gain of catalytic residue at P65 (P = 5e-04);

MVP

0.040

ClinPred

0.12

GERP RS

2.5

Varity_R

0.068

gMVP

0.27

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over