14-28767732-CGG-CGGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS2PVS1PM2_SupportingPS4

This summary comes from the ClinGen Evidence Repository: The p.Glu154Glyfs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu154Glyfs variant in FOXG1 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with FOXG1 disorder (PMID 19806373, 28661489, Internal database-GeneDx) (PS2_VS). The p.Glu154Glyfs variant has also has been observed in at least 10 other individuals with FOXG1 disorder (PMID 19806373, 24836831, 26344814, 28851325, 29595814, 29655203, 29322350, 28661489) (PS4). The p.Glu154Glyfs variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Glu154Glyfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PS2_VS, PS4, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199435/MONDO:0100040/016

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:24O:1

Conservation

PhyloP100: 2.76

Publications

28 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: Pathogenic. The variant received 17 ACMG points.

PVS1

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

PS2

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

PS4

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

PM2

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.460dupG	p.Glu154GlyfsTer301	frameshift	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.460dupG	p.Glu154GlyfsTer301	frameshift	Exon 1 of 1	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1		c.460dupG	p.Glu154GlyfsTer301	frameshift	Exon 2 of 2	ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1		n.374+1726dupG		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

130702

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000158

AC:

AN:

1268600

Hom.:

Cov.:

AF XY:

0.00000159

AC XY:

AN XY:

628114

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29588

American (AMR)

AF:

0.00

AC:

AN:

35130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23834

East Asian (EAS)

AF:

0.00

AC:

AN:

33982

South Asian (SAS)

AF:

0.00

AC:

AN:

76696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30340

Middle Eastern (MID)

AF:

0.000265

AC:

AN:

3768

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

981892

Other (OTH)

AF:

0.00

AC:

AN:

53370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Rett syndrome, congenital variant (17)

not provided (3)

FOXG1 disorder (2)

Abnormal cerebral morphology (1)

FOXG1-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=13/187

disease causing (ClinVar)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over