rs786205012

Positions:

• chr14-28767960-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3 PM2_Supporting PM1

This summary comes from the ClinGen Evidence Repository: The p.Asn227Lys variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asn227Lys variant in FOXG1 is absent from gnomAD (PM2_supporting). The p.Asn227Lys variant was observed in an individual with microcephaly, rocking movements, absent speech, epilepsy, bruxism, severe scoliosis, and who is non-ambulatory. However, this individual's parents were not available for segregation analysis and this individual was evaluated once at the age of 13 years old (PMID 19578037) (PP4_not met). In summary, the p.Asn227Lys variant in FOXG1 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM1, PP3, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199447/MONDO:0100040/033

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 3.93

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]

LINC01551 (HGNC:19828): (long intergenic non-protein coding RNA 1551)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.681C>G	p.Asn227Lys	missense_variant	1/1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.681C>G	p.Asn227Lys	missense_variant	1/1		NM_005249.5	ENSP00000339004	P1
FOXG1	ENST00000706482.1	c.681C>G	p.Asn227Lys	missense_variant	2/2			ENSP00000516406	P1
LINC01551	ENST00000675861.1	n.374+1947C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2021	This variant disrupts the p.Asn227 amino acid residue in FOXG1. Other variant(s) that disrupt this residue have been observed in individuals with FOXG1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt FOXG1 protein function. ClinVar contains an entry for this variant (Variation ID: 189623). This missense change has been observed in individual(s) with Rett syndrome, congenital variant (PMID: 19578037). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 227 of the FOXG1 protein (p.Asn227Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 20, 2018	- -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Jul 13, 2010	- -

FOXG1 disorder Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Apr 14, 2023	The p.Asn227Lys variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asn227Lys variant in FOXG1 is absent from gnomAD (PM2_supporting). The p.Asn227Lys variant was observed in an individual with microcephaly, rocking movements, absent speech, epilepsy, bruxism, severe scoliosis, and who is non-ambulatory. However, this individual's parents were not available for segregation analysis and this individual was evaluated once at the age of 13 years old (PMID 19578037) (PP4_not met). In summary, the p.Asn227Lys variant in FOXG1 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM1, PP3, PM2_supporting). -
Uncertain significance, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	May 10, 2024	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: met Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD v4 (PM2_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.87		Gain of methylation at N227 (P = 0.007);
MVP		1.0
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.99
gMVP		1.0

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

Other links and lift over

dbSNP: rs786205012; hg19: chr14-29237166;