14-28767417-GCACCACCACCACCAC-GCACCACCACCACCACCAC

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_005249.5(FOXG1):c.159_161dupCCA(p.His54dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,385,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H54H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.512

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.

BP3

Nonframeshift variant in repetitive region in NM_005249.5

BP6

Variant 14-28767417-G-GCAC is Benign according to our data. Variant chr14-28767417-G-GCAC is described in ClinVar as Likely_benign. ClinVar VariationId is 189606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.159_161dupCCA	p.His54dup	disruptive_inframe_insertion	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.159_161dupCCA	p.His54dup	disruptive_inframe_insertion	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1 link	c.159_161dupCCA	p.His54dup	disruptive_inframe_insertion	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1 link	n.374+1425_374+1427dupCCA		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

143126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000138

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000129

AC:

AN:

139964

AF XY:

0.000144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000271

Gnomad ASJ exome

AF:

0.000393

Gnomad EAS exome

AF:

0.000136

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000865

Gnomad OTH exome

AF:

0.000564

GnomAD4 exome

AF:

0.0000571

AC:

AN:

1242460

Hom.:

Cov.:

AF XY:

0.0000634

AC XY:

AN XY:

615180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25398

American (AMR)

AF:

0.000293

AC:

AN:

30692

Ashkenazi Jewish (ASJ)

AF:

0.000158

AC:

AN:

19030

East Asian (EAS)

AF:

0.000162

AC:

AN:

24694

South Asian (SAS)

AF:

0.0000137

AC:

AN:

72984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.0000460

AC:

AN:

977996

Other (OTH)

AF:

0.000192

AC:

AN:

46876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000105

AC:

AN:

143202

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

69516

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

39452

American (AMR)

AF:

0.00

AC:

AN:

14528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3340

East Asian (EAS)

AF:

0.00

AC:

AN:

4878

South Asian (SAS)

AF:

0.00

AC:

AN:

4532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.000138

AC:

AN:

65040

Other (OTH)

AF:

0.00

AC:

AN:

1958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

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:

0.0000874

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 18, 2012

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Apr 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FOXG1 c.159_161dupCCA (p.His57dup) results in an in-frame duplication that is predicted to duplicate one amino acid into the encoded protein. The variant allele was found at a frequency of 0.00013 in 139964 control chromosomes. The observed variant frequency is approximately 129 fold of the estimated maximal expected allele frequency for a pathogenic variant in FOXG1 causing Rett Syndrome, Congenital Variant phenotype (1e-06). To our knowledge, no occurrence of c.159_161dupCCA in individuals affected with Rett Syndrome, Congenital Variant and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 189606). Based on the evidence outlined above, the variant was classified as likely benign. -

FOXG1 disorder

Benign:1

May 08, 2024

Centre for Population Genomics, CPG

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD v4 is between 0.008% and 0.03% (BS1). Inframe expansions in FOXG1 repetitive regions (BP3) -

not provided

Benign:1

Sep 16, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22190898) -

FOXG1-related disorder

Benign:1

Feb 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Rett syndrome, congenital variant

Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.51

Mutation Taster

=79/21

polymorphism

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over