rs780242359

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BP5_Strong

This summary comes from the ClinGen Evidence Repository: The p.Ser425Pro variant in FOXG1 is present in one XX and one XY individual in gnomAD v2.1.1 (0.00176%) (not sufficient to meet BS1 criteria). The p.Ser425Pro variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ser425Pro variant is found in at least 3 patients with an alternate molecular basis of disease (GeneDx internal database) (BP5_Strong). In summary, the p.Ser425Pro variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS2, BP5_strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314592/MONDO:0100040/035

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

12
7

Clinical Significance

Benign reviewed by expert panel U:1B:3

Conservation

PhyloP100: 4.74
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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/exons MANE Protein UniProt
FOXG1NM_005249.5 linkuse as main transcriptc.1273T>C p.Ser425Pro missense_variant 1/1 ENST00000313071.7 NP_005240.3 P55316

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXG1ENST00000313071.7 linkuse as main transcriptc.1273T>C p.Ser425Pro missense_variant 1/16 NM_005249.5 ENSP00000339004.3 P55316
FOXG1ENST00000706482.1 linkuse as main transcriptc.1273T>C p.Ser425Pro missense_variant 2/2 ENSP00000516406.1 P55316
LINC01551ENST00000675861.1 linkuse as main transcriptn.374+2539T>C intron_variant

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251334
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135876
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461870
Hom.:
0
Cov.:
34
AF XY:
0.0000303
AC XY:
22
AN XY:
727240
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000423
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.0000724
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsApr 16, 2018- -
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 15, 2020- -
FOXG1 disorder Benign:1
Benign, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelApr 18, 2024The p.Ser425Pro variant in FOXG1 is present in one XX and one XY individual in gnomAD v2.1.1 (0.00176%) (not sufficient to meet BS1 criteria). The p.Ser425Pro variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ser425Pro variant is found in at least 3 patients with an alternate molecular basis of disease (GeneDx internal database) (BP5_Strong). In summary, the p.Ser425Pro variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS2, BP5_strong). -
Rett syndrome, congenital variant Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 18, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.42
T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.75
T
M_CAP
Uncertain
0.091
D
MetaRNN
Uncertain
0.69
D
MetaSVM
Uncertain
0.45
D
MutationAssessor
Benign
0.81
L
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.4
N
REVEL
Uncertain
0.53
Sift
Benign
0.070
T
Sift4G
Benign
0.19
T
Polyphen
0.99
D
Vest4
0.59
MVP
0.93
ClinPred
0.43
T
GERP RS
4.1
Varity_R
0.34
gMVP
0.57

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.

Other links and lift over

dbSNP: rs780242359; hg19: chr14-29237758; API