chr14-28767550-C-A

Position:

chr14-28767550-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005249.5(FOXG1):c.271C>A(p.Pro91Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000264 in 1,138,306 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.425

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FOXG1. . Trascript score misZ 3.7891 (greater than threshold 3.09). GenCC has associacion of gene with Rett syndrome, congenital variant, FOXG1 disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.16154295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5 linkuse as main transcript	c.271C>A	p.Pro91Thr	missense_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
FOXG1	ENST00000313071.7 linkuse as main transcript	c.271C>A	p.Pro91Thr	missense_variant	1/1	NM_005249.5	P1
FOXG1	ENST00000706482.1 linkuse as main transcript	c.271C>A	p.Pro91Thr	missense_variant	2/2		P1
LINC01551	ENST00000675861.1 linkuse as main transcript	n.374+1537C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000101

AC:

AN:

990052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

467216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000508

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:

0.0000135

AC:

AN:

148254

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72174

show subpopulations

Gnomad4 AFR

AF:

0.0000488

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rett syndrome, congenital variant

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 91 of the FOXG1 protein (p.Pro91Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 471468). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FOXG1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Feb 03, 2022	FOXG1 NM_005249.4 exon 1 p.Pro91Thr (c.271C>A): This variant has not been reported in the literature but is present in 0.004% (2/4100) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/14-28767550-C-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:471468). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.32

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.53

M_CAP

Benign

0.077

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.24

REVEL

Benign

0.030

Sift

Uncertain

0.0020

Sift4G

Benign

0.46

Polyphen

0.86

Vest4

0.047

MutPred

0.26

Gain of phosphorylation at P91 (P = 0.0056);

MVP

0.28

ClinPred

0.36

GERP RS

2.0

Varity_R

0.13

gMVP

0.30

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