Genetic Variant FOXG1:p.His52_His54del (chr14-28767417-GCACCACCAC-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP3BP6_Very_StrongBS2

The NM_005249.5(FOXG1):c.153_161delCCACCACCA(p.His52_His54del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,385,622 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. H51H) has been classified as Likely benign. The gene FOXG1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: 2.54

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:

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ACMG classification

Specifications for FOXG1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 9 uncertain in NM_005249.5

BP3

Nonframeshift variant in repetitive region in NM_005249.5

BP6

Variant 14-28767417-GCACCACCAC-G is Benign according to our data. Variant chr14-28767417-GCACCACCAC-G is described in ClinVar as Benign. ClinVar VariationId is 205462.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAdExome4 at 26 AD gene.

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.153_161delCCACCACCA	p.His52_His54del	disruptive_inframe_deletion	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.153_161delCCACCACCA	p.His52_His54del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1		c.153_161delCCACCACCA	p.His52_His54del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1		n.374+1419_374+1427delCCACCACCA		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000279

AC:

AN:

143126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000254

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:

0.0000461

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000143

AC:

AN:

139964

AF XY:

0.0000131

show subpopulations

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:

0.0000173

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000209

AC:

AN:

1242496

Hom.:

AF XY:

0.0000195

AC XY:

AN XY:

615206

show subpopulations

African (AFR)

AF:

0.0000394

AC:

AN:

25398

American (AMR)

AF:

0.0000326

AC:

AN:

30692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19030

East Asian (EAS)

AF:

0.00

AC:

AN:

24692

South Asian (SAS)

AF:

0.0000137

AC:

AN:

72990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40782

Middle Eastern (MID)

AF:

0.000250

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

978028

Other (OTH)

AF:

0.00

AC:

AN:

46876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000279

AC:

AN:

143126

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

69430

show subpopulations

African (AFR)

AF:

0.0000254

AC:

AN:

39358

American (AMR)

AF:

0.00

AC:

AN:

14508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3340

East Asian (EAS)

AF:

0.00

AC:

AN:

4890

South Asian (SAS)

AF:

0.00

AC:

AN:

4542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000461

AC:

AN:

65052

Other (OTH)

AF:

0.00

AC:

AN:

1936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

FOXG1 disorder (2)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=170/30

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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14-28767417-GCACCACCACCACCAC-GCACCAC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over