Genetic Variant NM_005249.5:c.455G>A (chr14-28767734-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005249.5(FOXG1):c.455G>A(p.Gly152Glu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G152A) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33581337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.455G>A	p.Gly152Glu	missense_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FOXG1	ENST00000313071.7 link	c.455G>A	p.Gly152Glu	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1 link	c.455G>A	p.Gly152Glu	missense_variant	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1 link	n.374+1721G>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1380480

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

680544

African (AFR)

AF:

0.00

AC:

AN:

31776

American (AMR)

AF:

0.00

AC:

AN:

35834

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25070

East Asian (EAS)

AF:

0.00

AC:

AN:

36018

South Asian (SAS)

AF:

0.00

AC:

AN:

79246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4074

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076934

Other (OTH)

AF:

0.00

AC:

AN:

57604

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 04, 2012

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly152Glu (GGG>GAG):c.455 G>A in exon 1 of the FOXG1 gene (NM_005249.3). The Gly152Glu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Gly152Glu in approximately 3,000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. This amino acid substitution is non-conservative, as an uncharged, non-polar Glycine residue is replaced by a negatively charged Glutamic acid residue. Gly152Glu alters a position that is not conserved through evolution, and it does not occur within the forkhead binding domain where all previously reported missense mutations in FOXG1 have been identified. Additionally, several in silico algorithms predict Gly152Glu may be benign. Therefore, based on the currently available information, it is unclear whether Gly152Glu is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.41

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.34

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

1.0

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

0.66

REVEL

Benign

0.058

Sift

Benign

0.045

Sift4G

Benign

0.19

Polyphen

0.99

Vest4

0.16

MutPred

0.31

Gain of solvent accessibility (P = 0.0789);

MVP

0.30

ClinPred

0.44

GERP RS

1.4

Varity_R

0.087

gMVP

0.38

Mutation Taster

=93/7

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