rs1555321294

Positions:

• chr14-28767778-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005249.5(FOXG1):​c.500del​(p.Glu167GlyfsTer25) variant causes a frameshift change. 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. E167E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.50

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 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 210 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-28767778-GA-G is Pathogenic according to our data. Variant chr14-28767778-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 471469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5	c.500del	p.Glu167GlyfsTer25	frameshift_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXG1	ENST00000313071.7	c.500del	p.Glu167GlyfsTer25	frameshift_variant	1/1		NM_005249.5	P1
FOXG1	ENST00000706482.1	c.500del	p.Glu167GlyfsTer25	frameshift_variant	2/2			P1
LINC01551	ENST00000675861.1	n.374+1766del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Mar 23, 2022	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 30, 2017	For these reasons, this variant has been classified as Pathogenic. A different truncation downstream of this variant (p.Gly169Alafs*23) has been determined to be pathogenic (PMID: 25356899, Invitae). 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 a FOXG1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FOXG1 gene (p.Glu167Glyfs*25). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 323 amino acids of the FOXG1 protein. -

Computational scores

Source: dbNSFP v4.3

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: rs1555321294; hg19: chr14-29236984;