NM_005249.5:c.256delC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP4PM6_StrongPM2_SupportingPS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Gln86Argfs 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.Gln86Argfs variant in FOXG1 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with FOXG1 disorder (PMID 22739344, 2634418) (PM6_strong, PP4). This variant has been observed in at least 3 other individuals with FOXG1 disorder (PMID 22739344, 26344814) (PS4_moderate). The c.256delC variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Gln86Argfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199433/MONDO:0100040/016

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: -0.607

Publications

10 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 16 ACMG points.

PVS1

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.

PM6

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

PP4

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.256delC	p.Gln86ArgfsTer106	frameshift	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.256delC	p.Gln86ArgfsTer106	frameshift	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.256delC	p.Gln86ArgfsTer106	frameshift	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1522delC		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

31

GnomAD2 exomes

AF:

0.00

AC:

0

AN:

530

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ 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:

0.00000985

AC:

9

AN:

913394

Hom.:

0

Cov.:

16

AF XY:

0.0000139

AC XY:

6

AN XY:

430168

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:

0

AN:

17750

American (AMR)

AF:

0.000256

AC:

1

AN:

3902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

8156

East Asian (EAS)

AF:

0.000174

AC:

2

AN:

11474

South Asian (SAS)

AF:

0.00

AC:

0

AN:

17912

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

11280

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

2104

European-Non Finnish (NFE)

AF:

0.00000743

AC:

6

AN:

807964

Other (OTH)

AF:

0.00

AC:

0

AN:

32852

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.231

Heterozygous variant carriers

0

2

4

5

7

9

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<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.:

31

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

6

-

-

Rett syndrome, congenital variant (6)

3

-

-

FOXG1 disorder (3)

1

-

-

not provided (1)

1

-

-

Rett syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.61

Mutation Taster

=0/200

disease causing (ClinVar)

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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Other links and lift over

dbSNP: rs786205001; hg19: chr14-29236734; API