14-28767449-ACCCGCCGCCG-ACCCGCCGCCGCCCGCCGCCG

Variant names:

• chr14-28767449-A-ACCCGCCGCCG
• rs1555321206
• NM_005249.5:c.177_186dupGCCGCCCGCC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005249.5(FOXG1):​c.177_186dupGCCGCCCGCC​(p.Pro63AlafsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. P63P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXG1 NM_005249.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 0.387
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 265 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-28767449-A-ACCCGCCGCCG is Pathogenic according to our data. Variant chr14-28767449-A-ACCCGCCGCCG is described in ClinVar as Pathogenic. ClinVar VariationId is 451937.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.177_186dupGCCGCCCGCC	p.Pro63AlafsTer61	frameshift_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.177_186dupGCCGCCCGCC	p.Pro63AlafsTer61	frameshift_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.177_186dupGCCGCCCGCC	p.Pro63AlafsTer61	frameshift_variant	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1443_374+1452dupGCCGCCCGCC		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

FOXG1 disorder Pathogenic:1

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Pro63Alafs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Pro63Alafs variant in FOXG1 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with FOXG1-associated disorder (Internal database - GeneDx) (PS2). The p.Pro63Alafs variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Pro63Alafs variant in FOXG1 is classified as Pathogenic for FOXG1-associated disorder based on the ACMG/AMP criteria (PVS1, PS2, PM2_supporting). -

not provided Pathogenic:1

Sep 13, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.177_186dup10 variant in the FOXG1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.177_186dup10 variant causes a frameshift starting with codon Proline 63, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 61 of the new reading frame, denoted p.Pro63AlafsX61. This variant is predicted to cause loss of normal protein function through protein truncation. The c.177_186dup10 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.177_186dup10 as a pathogenic variant. -

Rett syndrome, congenital variant Pathogenic:1

Sep 24, 2017

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. Multiple truncations downstream of this variant have been determined to be pathogenic (PMID: 24836831). This suggests that deletion of this region of the FOXG1 protein is causative of disease. This variant has not been reported in the literature in individuals with FOXG1-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the FOXG1 gene (p.Pro63Alafs*61). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 427 amino acids of the FOXG1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555321206; hg19: chr14-29236655;