rs727503935

Variant names:

• chr14-28767949-G-A
• rs727503935
• NM_005249.5:c.670G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS4_Moderate PM1 PS3_Supporting PM6 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Gly224Ser variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID:18571142, 28661489) (PM1). The p.Gly224Ser variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with gross motor delay and infantile spasms (Internal database - GeneDx) (PM6). Functional study has shown that this variant impacts protein function (PMID:35163265) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Gly224Ser variant in FOXG1 is absent from gnomAD v4.1.0 (PM2_Supporting). The p.Gly224Ser variant has been observed in 3 individuals with neurodevelopmental disease (PMID:30533527, Internal database - GeneDx, Internal database - University of Chicago) (PS4_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic based on ACMG/AMP criteria (PM1, PM6, PS3_supporting, PP3_supporting, PM2_supporting, PS4_moderate). (FOXG1 specification v3.0.0; approved on 12/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA234034/MONDO:0100040/035

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.97
• Publications: 2 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

Specifications for FOXG1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005249.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.670G>A	p.Gly224Ser	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.670G>A	p.Gly224Ser	missense	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.670G>A	p.Gly224Ser	missense	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1936G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000268 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	FOXG1 disorder (4)
2	-	-	not provided (2)
1	-	-	Rett syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.57		Gain of catalytic residue at I229 (P = 0.0159)
MVP		1.0
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727503935; hg19: chr14-29237155;