rs796052453

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BA1BP4BP5_StrongBS2

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

Clinical Significance

Benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: -0.424

Publications

0 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005249.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.245C>A	p.Pro82Gln	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.245C>A	p.Pro82Gln	missense	Exon 1 of 1	ENSP00000339004.3
FOXG1	ENST00000706482.1		c.245C>A	p.Pro82Gln	missense	Exon 2 of 2	ENSP00000516406.1
LINC01551	ENST00000675861.1		n.374+1511C>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000265

AC:

AN:

147052

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

514

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000221

AC:

AN:

904362

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

425954

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

17448

American (AMR)

AF:

0.00

AC:

AN:

3614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7780

East Asian (EAS)

AF:

0.00

AC:

AN:

10480

South Asian (SAS)

AF:

0.00

AC:

AN:

17828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2050

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

802714

Other (OTH)

AF:

0.00

AC:

AN:

32192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000265

AC:

AN:

147154

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

AN XY:

71630

show subpopulations

African (AFR)

AF:

0.000904

AC:

AN:

40912

American (AMR)

AF:

0.0000675

AC:

AN:

14816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66170

Other (OTH)

AF:

0.000488

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

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.

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)

not provided

Benign:1

Nov 08, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.32

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.42

M_CAP

Benign

0.030

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

PhyloP100

-0.42

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.020

REVEL

Benign

0.011

Sift

Benign

0.24

Sift4G

Benign

0.61

Polyphen

0.39

Vest4

0.17

MutPred

0.31

Gain of catalytic residue at P84 (P = 0.001)

MVP

0.16

ClinPred

0.24

GERP RS

1.2

Varity_R

0.085

gMVP

0.19

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over