chr14-28767524-C-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BS2BA1BP4BP5_Strong

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Pro82Gln variant in FOXG1 in gnomAD v2.1.1 is 0.00087 in the African/African American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Pro82Gln variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Pro82Gln variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). Computational analysis prediction tools suggest that the p.Pro82Gln variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro82Gln variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong, BP4). (FOXG1 specification v.3; approved on 8/30/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA314578/MONDO:0100040/035

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

1
18

Clinical Significance

Benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: -0.424
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]
LINC01551 (HGNC:19828): (long intergenic non-protein coding RNA 1551)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

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.
BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXG1NM_005249.5 linkc.245C>A p.Pro82Gln missense_variant Exon 1 of 1 ENST00000313071.7 NP_005240.3 P55316

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXG1ENST00000313071.7 linkc.245C>A p.Pro82Gln missense_variant Exon 1 of 1 6 NM_005249.5 ENSP00000339004.3 P55316
FOXG1ENST00000706482.1 linkc.245C>A p.Pro82Gln missense_variant Exon 2 of 2 ENSP00000516406.1 P55316
LINC01551ENST00000675861.1 linkn.374+1511C>A intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
AF:
0.000265
AC:
39
AN:
147052
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000907
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000676
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:
0.00
Gnomad OTH
AF:
0.000494
GnomAD4 exome
AF:
0.0000221
AC:
20
AN:
904362
Hom.:
0
Cov.:
17
AF XY:
0.0000282
AC XY:
12
AN XY:
425954
show subpopulations
Gnomad4 AFR exome
AF:
0.00115
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000265
AC:
39
AN:
147154
Hom.:
0
Cov.:
31
AF XY:
0.000251
AC XY:
18
AN XY:
71630
show subpopulations
Gnomad4 AFR
AF:
0.000904
Gnomad4 AMR
AF:
0.0000675
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000488
Bravo
AF:
0.000272

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Jan 23, 2019
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 14, 2016
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Nov 14, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1
Nov 08, 2019
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

FOXG1 disorder Benign:1
Aug 30, 2024
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The highest population minor allele frequency of the p.Pro82Gln variant in FOXG1 in gnomAD v2.1.1 is 0.00087 in the African/African American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Pro82Gln variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Pro82Gln variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). Computational analysis prediction tools suggest that the p.Pro82Gln variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro82Gln variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong, BP4). (FOXG1 specification v.3; approved on 8/30/2024) -

Rett syndrome, congenital variant Benign:1
Nov 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.32
T
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.064
N
LIST_S2
Benign
0.42
T
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.074
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.34
N
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
0.020
N
REVEL
Benign
0.011
Sift
Benign
0.24
T
Sift4G
Benign
0.61
T
Polyphen
0.39
B
Vest4
0.17
MutPred
0.31
Gain of catalytic residue at P84 (P = 0.001);
MVP
0.16
ClinPred
0.24
T
GERP RS
1.2
Varity_R
0.085
gMVP
0.19

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: rs796052453; hg19: chr14-29236730; API