NM_005249.5:c.455G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4BP5_StrongBS1BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Gly152Ala variant in FOXG1 is 0.008% in Latino sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly152Ala variant is observed in at least 20 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2).The p.Gly152Ala variant is found in at least 4 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). Computational analysis prediction tools suggest that the p.Gly152Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gly152Ala variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA389475129/MONDO:0100040/035

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:4

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005249.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.455G>C	p.Gly152Ala	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.455G>C	p.Gly152Ala	missense	Exon 1 of 1	ENSP00000339004.3
FOXG1	ENST00000706482.1		c.455G>C	p.Gly152Ala	missense	Exon 2 of 2	ENSP00000516406.1
LINC01551	ENST00000675861.1		n.374+1721G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151318

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000149

AC:

AN:

134034

AF XY:

0.0000136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000813

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

AF:

0.0000420

AC:

AN:

1380480

Hom.:

Cov.:

AF XY:

0.0000470

AC XY:

AN XY:

680544

show subpopulations

African (AFR)

AF:

0.0000315

AC:

AN:

31776

American (AMR)

AF:

0.000112

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:

0.0000483

AC:

AN:

1076934

Other (OTH)

AF:

0.0000174

AC:

AN:

57604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000397

AC:

AN:

151318

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

73858

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41346

American (AMR)

AF:

0.000197

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

67582

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 10, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Dec 16, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

FOXG1 disorder

Benign:1

Oct 13, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the p.Gly152Ala variant in FOXG1 is 0.008% in Latino sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly152Ala variant is observed in at least 20 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2).The p.Gly152Ala variant is found in at least 4 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). Computational analysis prediction tools suggest that the p.Gly152Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gly152Ala variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong, BP4).

not provided

Benign:1

Jun 11, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Rett syndrome, congenital variant

Benign:1

Aug 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.32

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

1.0

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

0.020

REVEL

Benign

0.063

Sift

Benign

0.17

Sift4G

Benign

0.26

Polyphen

0.95

Vest4

0.17

MutPred

0.31

Loss of loop (P = 0.0374)

MVP

0.13

ClinPred

0.22

GERP RS

1.4

Varity_R

0.064

gMVP

0.44

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over