Genetic Variant FOXG1:p.Val10Met (chr14-28767307-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005249.5(FOXG1):c.28G>A(p.Val10Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000145 in 1,306,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19327012).

BS2

High AC in GnomAdExome4 at 19 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.28G>A	p.Val10Met	missense	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.28G>A	p.Val10Met	missense	Exon 1 of 1	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1		c.28G>A	p.Val10Met	missense	Exon 2 of 2	ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1		n.374+1294G>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000494

AC:

AN:

202422

AF XY:

0.00000905

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000348

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:

0.0000145

AC:

AN:

1306650

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

649436

show subpopulations

African (AFR)

AF:

0.0000367

AC:

AN:

27236

American (AMR)

AF:

0.0000277

AC:

AN:

36058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20088

East Asian (EAS)

AF:

0.00

AC:

AN:

28358

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4992

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

1015330

Other (OTH)

AF:

0.0000200

AC:

AN:

49926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Rett syndrome, congenital variant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Benign

0.074

Eigen_PC

Benign

0.049

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.81

PhyloP100

4.6

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.29

REVEL

Benign

0.10

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.010

Polyphen

0.97

Vest4

0.14

MutPred

0.32

Loss of methylation at K11 (P = 0.0206)

MVP

0.46

ClinPred

0.48

GERP RS

2.0

Varity_R

0.12

gMVP

0.68

Mutation Taster

=85/15

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over