rs1057520147

Positions:

chr14-28767554-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. BS2_SupportingBP5PM2_SupportingBP4

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

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

BP4

BP5

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5 linkuse as main transcript	c.275C>T	p.Ala92Val	missense_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
FOXG1	ENST00000313071.7 linkuse as main transcript	c.275C>T	p.Ala92Val	missense_variant	1/1	NM_005249.5	P1
FOXG1	ENST00000706482.1 linkuse as main transcript	c.275C>T	p.Ala92Val	missense_variant	2/2		P1
LINC01551	ENST00000675861.1 linkuse as main transcript	n.374+1541C>T		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000525

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000717

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000674

AC:

AN:

148422

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000150

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 28, 2016

- -

FOXG1 disorder

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Oct 13, 2023

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2022

- -

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

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

MutationTaster

Benign

0.83

N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over