rs786204998

Variant names:

• chr14-28767923-TC-CT
• rs786204998
• NM_005249.5:c.644_645delTCinsCT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_Very_Strong

The NM_005249.5(FOXG1):​c.644_645delTCinsCT​(p.Phe215Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F215L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.87
• Publications: 1 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 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_005249.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-28767924-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 373043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 14-28767923-TC-CT is Pathogenic according to our data. Variant chr14-28767923-TC-CT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 211034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.644_645delTCinsCT	p.Phe215Ser	missense_variant		ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.644_645delTCinsCT	p.Phe215Ser	missense_variant		6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.644_645delTCinsCT	p.Phe215Ser	missense_variant				ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1910_374+1911delTCinsCT		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FOXG1 disorder Pathogenic:1

May 31, 2024

Centre for Population Genomics, CPG

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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 pathogenic. At least the following criteria are met: >=2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). Variation ID: 1068106 , Decipher Patient 271213, Variation ID: 3024521 This variant has been identified as a de novo occurrence in an individual with FOXG1 disorder with confirmed parental relationships (PS2) (Decipher Patient: 292136) Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). This variant is absent from gnomAD (PM2_Supporting). -

Rett syndrome, congenital variant Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/100	disease causing

Splicing

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

Other links and lift over

dbSNP: rs786204998; hg19: chr14-29237129;