14-28767840-C-G

Variant names:

• chr14-28767840-C-G
• rs796052462
• NM_005249.5:c.561C>G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_005249.5(FOXG1):​c.561C>G​(p.Asn187Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.81

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 Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_005249.5 (FOXG1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a DNA_binding_region Fork-head (size 94) in uniprot entity FOXG1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_005249.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the FOXG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 90 curated pathogenic missense variants (we use a threshold of 10). The gene has 66 curated benign missense variants. Trascript score misZ: 3.7891 (above the threshold of 3.09). GenCC associations: The gene is linked to Rett syndrome, congenital variant, FOXG1 disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 14-28767840-C-G is Pathogenic according to our data. Variant chr14-28767840-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 265363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-28767840-C-G is described in Lovd as [Likely_pathogenic]. Variant chr14-28767840-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.561C>G	p.Asn187Lys	missense_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.561C>G	p.Asn187Lys	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.561C>G	p.Asn187Lys	missense_variant	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1827C>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Apr 16, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 10, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N187K variant, resulting from a different nucleotide substitution (c.561 C>A), has been reported previously as a de novo variant in a patient referred for clinical whole exome sequencing (Farwell et al., 2015). Additionally, the N187K variant has been identified as a de novo variant in another patient with epilepsy at GeneDx. The N187K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N187K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a conserved position predicted to occur within the forkhead binding domain of the FOXG1 protein where all previously reported missense variants in FOXG1 have been identified. A different missense variant in the same codon (N187D) as well as missense variants in nearby residues (L189V, M191R) have been reported in the Human Gene Mutation Database in association with FOXG1-related disorders (Stenson et al., 2014). -

Rett syndrome, congenital variant Pathogenic:1

Mar 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FOXG1 protein function. ClinVar contains an entry for this variant (Variation ID: 265363). This missense change has been observed in individual(s) with clinical features of FOXG1-related conditions (PMID: 28628100, 28661489). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 187 of the FOXG1 protein (p.Asn187Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.66		Gain of catalytic residue at P182 (P = 2e-04);
MVP		0.97
ClinPred		1.0	D
GERP RS		1.8
Varity_R		0.91
gMVP		0.99

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: rs796052462; hg19: chr14-29237046;