14-28767471-ACCGCCGCCGCCGCCGCAGCAGCAGCAG-ACCGCCGCCGCCGCCGCAGCAGCAGCAGCCGCCGCCGCCGCCGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_005249.5(FOXG1):c.209_235dupAGCAGCAGCAGCCGCCGCCGCCGCCGC(p.Gln70_Pro78dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 128,986 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXG1
NM_005249.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:3

Conservation

PhyloP100: 1.26

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005249.5

BP6

Variant 14-28767471-A-ACCGCCGCCGCCGCCGCAGCAGCAGCAG is Benign according to our data. Variant chr14-28767471-A-ACCGCCGCCGCCGCCGCAGCAGCAGCAG is described in ClinVar as Benign. ClinVar VariationId is 421833.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000357 (46/128986) while in subpopulation AFR AF = 0.00121 (42/34820). AF 95% confidence interval is 0.000916. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.209_235dupAGCAGCAGCAGCCGCCGCCGCCGCCGC	p.Gln70_Pro78dup	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.209_235dupAGCAGCAGCAGCCGCCGCCGCCGCCGC	p.Gln70_Pro78dup	disruptive_inframe_insertion	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1 link	c.209_235dupAGCAGCAGCAGCCGCCGCCGCCGCCGC	p.Gln70_Pro78dup	disruptive_inframe_insertion	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1 link	n.374+1475_374+1501dupAGCAGCAGCAGCCGCCGCCGCCGCCGC		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000357

AC:

AN:

128904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000152

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:

0.00

Gnomad OTH

AF:

0.00113

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000104

AC:

AN:

962094

Hom.:

Cov.:

AF XY:

0.0000128

AC XY:

AN XY:

467336

show subpopulations

African (AFR)

AF:

0.000460

AC:

AN:

19562

American (AMR)

AF:

0.00

AC:

AN:

18808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13410

East Asian (EAS)

AF:

0.00

AC:

AN:

13832

South Asian (SAS)

AF:

0.0000261

AC:

AN:

38326

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2352

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

804290

Other (OTH)

AF:

0.00

AC:

AN:

34458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.635

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:

0.000357

AC:

AN:

128986

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

AN XY:

62816

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

34820

American (AMR)

AF:

0.000151

AC:

AN:

13208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3086

East Asian (EAS)

AF:

0.00

AC:

AN:

4266

South Asian (SAS)

AF:

0.00

AC:

AN:

3954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

59870

Other (OTH)

AF:

0.00112

AC:

AN:

1788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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.:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 14, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.209_235dup27 variant (also known as p.Q70_P78dup), located in coding exon 1 of the FOXG1 gene, results from an in-frame duplication of 27 nucleotides at nucleotide positions 209 to 235. This results in the duplication of 9 extra residues (QQQQPPPPP) between codons 70 and 78. This variant did not co-segregate with disease in one individual tested in our laboratory. These amino acid positions are not conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

FOXG1 disorder

Benign:1

Dec 06, 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.Gln70_Pro78dup variant in FOXG1 is 0.09% in the African sub population in gnomAD v4, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). This variant was observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). Additionally, the p.Gln70_Pro78dup variant is an in-frame duplication present in a repetitive region of FOXG1 (BP3). In summary, the p.Gln70_Pro78dup variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2_supporting, BP3).

not provided

Benign:1

Jan 07, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Rett syndrome, congenital variant

Benign:1

Dec 28, 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

1.3

Mutation Taster

=83/17

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