chr14-28767488-A-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BP4BA1

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Gln70Pro variant in FOXG1 in gnomAD v4.1 is 0.00033 in the Admixed 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.Gln70Pro variant is observed in at least 2 unaffected individuals (Internal database - Ambry) (BS2). Computational analysis prediction tools suggest that the p.Gln70Pro variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gln70Pro variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294776/MONDO:0100040/035

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: 0.693

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

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
FOXG1	NM_005249.5 link	c.209A>C	p.Gln70Pro	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.209A>C	p.Gln70Pro	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1 link	c.209A>C	p.Gln70Pro	missense_variant	Exon 2 of 2			ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1 link	n.374+1475A>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000272

AC:

AN:

139852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000781

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000773

Gnomad ASJ

AF:

0.000307

Gnomad EAS

AF:

0.000846

Gnomad SAS

AF:

0.000224

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00370

Gnomad NFE

AF:

0.000219

Gnomad OTH

AF:

0.00157

GnomAD3 exomes

AF:

0.000138

AC:

AN:

36220

Hom.:

AF XY:

0.000178

AC XY:

AN XY:

22444

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:

0.000348

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

132

AN:

871366

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

418988

show subpopulations

Gnomad4 AFR exome

AF:

0.000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000950

Gnomad4 SAS exome

AF:

0.000195

Gnomad4 FIN exome

AF:

0.0000827

Gnomad4 NFE exome

AF:

0.000152

Gnomad4 OTH exome

AF:

0.000164

GnomAD4 genome

AF:

0.000264

AC:

AN:

139948

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

68106

show subpopulations

Gnomad4 AFR

AF:

0.0000779

Gnomad4 AMR

AF:

0.000772

Gnomad4 ASJ

AF:

0.000307

Gnomad4 EAS

AF:

0.000849

Gnomad4 SAS

AF:

0.000224

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000219

Gnomad4 OTH

AF:

0.00155

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000366

ExAC

AF:

0.0000714

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome, congenital variant

Uncertain:1Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Dec 01, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 06, 2017

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. -

FOXG1 disorder

Benign:1

Jun 25, 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.Gln70Pro variant in FOXG1 in gnomAD v4.1 is 0.00033 in the Admixed 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.Gln70Pro variant is observed in at least 2 unaffected individuals (Internal database - Ambry) (BS2). Computational analysis prediction tools suggest that the p.Gln70Pro variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gln70Pro variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.32

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.35

M_CAP

Benign

0.074

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.37

REVEL

Benign

0.035

Sift

Benign

0.35

Sift4G

Benign

0.29

Polyphen

0.80

Vest4

0.33

MutPred

0.32

Gain of catalytic residue at P65 (P = 5e-04);

MVP

0.040

ClinPred

0.041

GERP RS

0.93

Varity_R

0.089

gMVP

0.16

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