14-28767530-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2BP4BP5_Strong

This summary comes from the ClinGen Evidence Repository: The p.Pro84His variant in FOXG1 is present in 1 individual in gnomAD (0.0039%) (not sufficient to meet BS1 criteria). The p.Pro84His variant is observed in at least 20 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro84His variant is found in at least 4 patients with an alternate molecular basis of disease (internal database - Invitae; internal database - GeneDx) (BP5_strong). Computational analysis prediction tools suggest that the p.Pro84His variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro84His variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS2, BP5_strong, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16606972/MONDO:0100040/035

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:4

Conservation

PhyloP100: 0.467

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 Benign. Variant got -9 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.251C>A	p.Pro84His	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.251C>A	p.Pro84His	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1 link	c.251C>A	p.Pro84His	missense_variant	Exon 2 of 2			ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1 link	n.374+1517C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000204

AC:

AN:

147192

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:

0.0000453

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

919386

Hom.:

Cov.:

AF XY:

0.0000162

AC XY:

AN XY:

432900

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000302

GnomAD4 genome

AF:

0.0000204

AC:

AN:

147192

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71600

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:

0.0000453

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 30, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.251C>A (p.P84H) alteration is located in exon 1 (coding exon 1) of the FOXG1 gene. This alteration results from a C to A substitution at nucleotide position 251, causing the proline (P) at amino acid position 84 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

May 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FOXG1 c.251C>A (p.Pro84His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 1066578 control chromosomes. The observed variant frequency is approximately 15.94 fold of the estimated maximal expected allele frequency for a pathogenic variant in FOXG1 causing Rett Syndrome, Congenital Variant phenotype (1e-06). To our knowledge, no occurrence of c.251C>A in individuals affected with Rett Syndrome, Congenital Variant and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 380242). Based on the evidence outlined above, the variant was classified as likely benign. -

FOXG1 disorder

Benign:1

Oct 13, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The p.Pro84His variant in FOXG1 is present in 1 individual in gnomAD (0.0039%) (not sufficient to meet BS1 criteria). The p.Pro84His variant is observed in at least 20 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro84His variant is found in at least 4 patients with an alternate molecular basis of disease (internal database - Invitae; internal database - GeneDx) (BP5_strong). Computational analysis prediction tools suggest that the p.Pro84His variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro84His variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS2, BP5_strong, BP4). -

Rett syndrome, congenital variant

Benign:1

Oct 22, 2024

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

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.42

M_CAP

Benign

0.043

MetaRNN

Benign

0.095

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.32

REVEL

Benign

0.015

Sift

Uncertain

0.0030

Sift4G

Benign

0.12

Polyphen

0.15

Vest4

0.12

MutPred

0.28

Gain of catalytic residue at P79 (P = 0.0047);

MVP

0.21

ClinPred

0.26

GERP RS

2.0

Varity_R

0.18

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