dbSNP rs1424025007: FOXG1:p.Lys157del (chr14-28767742-GAGA-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_005249.5(FOXG1):c.469_471delAAG(p.Lys157del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000427 in 1,380,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K157K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.74

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005249.5

BS2

High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.469_471delAAG	p.Lys157del	conservative_inframe_deletion	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.469_471delAAG	p.Lys157del	conservative_inframe_deletion	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1 link	c.469_471delAAG	p.Lys157del	conservative_inframe_deletion	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1 link	n.374+1735_374+1737delAAG		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000140

AC:

AN:

142848

AF XY:

0.0000128

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:

0.0000351

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000427

AC:

AN:

1380232

Hom.:

AF XY:

0.0000411

AC XY:

AN XY:

680924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31904

American (AMR)

AF:

0.00

AC:

AN:

36326

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25108

East Asian (EAS)

AF:

0.00

AC:

AN:

36452

South Asian (SAS)

AF:

0.00

AC:

AN:

79532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.0000530

AC:

AN:

1074630

Other (OTH)

AF:

0.0000347

AC:

AN:

57624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rett syndrome, congenital variant

Uncertain:1

Oct 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. In summary, this is a novel in-frame deletion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FOXG1-related disease. This sequence change deletes 3 nucleotides from exon 1 of the FOXG1 mRNA (c.469_471delAAG). This leads to the deletion of 1 amino acid residuein the FOXG1 protein (p.Lys157del) but otherwise preserves the integrity of the reading frame.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.7

Mutation Taster

=74/26

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over