Variant 14-28767485-CGCAGCA-CGCAGCAGCA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_005249.5(FOXG1):c.218_220dup(p.Gln73dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,055,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. P69P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 inframe_insertion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: -0.214

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 14-28767485-C-CGCA is Benign according to our data. Variant chr14-28767485-C-CGCA is described in ClinVar as [Benign]. Clinvar id is 95265.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5 linkuse as main transcript	c.218_220dup	p.Gln73dup	inframe_insertion	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
FOXG1	ENST00000313071.7 linkuse as main transcript	c.218_220dup	p.Gln73dup	inframe_insertion	1/1	NM_005249.5	P1
FOXG1	ENST00000706482.1 linkuse as main transcript	c.218_220dup	p.Gln73dup	inframe_insertion	2/2		P1
LINC01551	ENST00000675861.1 linkuse as main transcript	n.374+1484_374+1486dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000306

AC:

AN:

143906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000687

Gnomad ASJ

AF:

0.00271

Gnomad EAS

AF:

0.000202

Gnomad SAS

AF:

0.000429

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000337

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

62992

Hom.:

AF XY:

0.00

AC XY:

AN XY:

36444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000184

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000733

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000212

AC:

193

AN:

911142

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

106

AN XY:

440340

show subpopulations

Gnomad4 AFR exome

AF:

0.0000548

Gnomad4 AMR exome

AF:

0.0000598

Gnomad4 ASJ exome

AF:

0.00118

Gnomad4 EAS exome

AF:

0.0000884

Gnomad4 SAS exome

AF:

0.0000899

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.000186

GnomAD4 genome

AF:

0.000306

AC:

AN:

143994

Hom.:

Cov.:

AF XY:

0.000328

AC XY:

AN XY:

70064

show subpopulations

Gnomad4 AFR

AF:

0.000226

Gnomad4 AMR

AF:

0.0000686

Gnomad4 ASJ

AF:

0.00271

Gnomad4 EAS

AF:

0.000203

Gnomad4 SAS

AF:

0.000429

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2012	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FOXG1: BP3, BS1, BS2 -

Rett syndrome, congenital variant

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 03, 2016	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2014

The variant is found in EPILEPSY panel(s). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2016

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

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Aug 25, 2022

The allele frequency of the p.Gln73dup variant in FOXG1 is 0.008% in European (non-Finnish) 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.Gln73dup variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Gln73dup variant is an in-frame duplication present in a repetitive region of FOXG1 (BP3). In summary, the p.Gln73dup variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP3). -

FOXG1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2023

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over