rs796052453

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_005249.5(FOXG1):c.245C>A(p.Pro82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000561 in 1,051,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P82P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

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]

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 -10 ACMG points.

PP2

Missense variant where missense usually causes diseases, FOXG1

BP4

Computational evidence support a benign effect (MetaRNN=0.07372302).

BP6

Variant 14-28767524-C-A is Benign according to our data. Variant chr14-28767524-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205469.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000221 (20/904362) while in subpopulation AFR AF= 0.00115 (20/17448). AF 95% confidence interval is 0.000759. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 17. This position pass quality control queck.

BS2

High AC in GnomAd at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5 linkuse as main transcript	c.245C>A	p.Pro82Gln	missense_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
FOXG1	ENST00000313071.7 linkuse as main transcript	c.245C>A	p.Pro82Gln	missense_variant	1/1	NM_005249.5	P1
FOXG1	ENST00000706482.1 linkuse as main transcript	c.245C>A	p.Pro82Gln	missense_variant	2/2		P1
LINC01551	ENST00000675861.1 linkuse as main transcript	n.374+1511C>A		intron_variant, non_coding_transcript_variant

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

GnomAD4 exome

AF:

0.0000221

AC:

AN:

904362

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

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:

AN:

147154

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 23, 2019	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2019

- -

Rett syndrome, congenital variant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

Cadd

Benign

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

MutationTaster

Benign

1.0

N;N

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

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