chr14-28767554-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. BP4BS2_SupportingBP5PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Ala92Val variant in FOXG1 is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). The p.Ala92Val variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - Invitae) (BP5). Computational analysis prediction tools suggest that the p.Ala92Val variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Ala92Val variant in FOXG1 is absent from gnomAD (PM2_supporting).In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 1 unaffected individual and 2 individuals with an alternate molecular diagnosis, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified this variant as Likely Benign (BS2_supporting, BP4, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16603285/MONDO:0100040/035

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: -0.593

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 -2 ACMG points.

PM2

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

BP4

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

BP5

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

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.275C>T	p.Ala92Val	missense_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3	P55316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXG1	ENST00000313071.7 link	c.275C>T	p.Ala92Val	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1 link	c.275C>T	p.Ala92Val	missense_variant	Exon 2 of 2			ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1 link	n.374+1541C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00000674

AC:

AN:

148422

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000631

AC:

AN:

998534

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

471568

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20070

American (AMR)

AF:

0.00

AC:

AN:

6418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11064

East Asian (EAS)

AF:

0.00

AC:

AN:

19310

South Asian (SAS)

AF:

0.0000525

AC:

AN:

19040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2520

European-Non Finnish (NFE)

AF:

0.0000717

AC:

AN:

864498

Other (OTH)

AF:

0.00

AC:

AN:

37948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00000674

AC:

AN:

148422

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40970

American (AMR)

AF:

0.00

AC:

AN:

14918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66732

Other (OTH)

AF:

0.00

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 28, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FOXG1 disorder

Benign:1

Oct 13, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The p.Ala92Val variant in FOXG1 is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). The p.Ala92Val variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - Invitae) (BP5). Computational analysis prediction tools suggest that the p.Ala92Val variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Ala92Val variant in FOXG1 is absent from gnomAD (PM2_supporting). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 1 unaffected individual and 2 individuals with an alternate molecular diagnosis, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified this variant as Likely Benign (BS2_supporting, BP4, BP5). -

Rett syndrome, congenital variant

Benign:1

Oct 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.56

M_CAP

Benign

0.049

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.59

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.21

REVEL

Benign

0.018

Sift

Uncertain

0.015

Sift4G

Benign

0.27

Polyphen

0.0040

Vest4

0.024

MutPred

0.28

Gain of catalytic residue at R88 (P = 0.0196);

MVP

0.14

ClinPred

0.14

GERP RS

2.0

Varity_R

0.090

gMVP

0.098

Mutation Taster

=92/8

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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