rs1064797186

Variant names:

• chr14-28767964-A-C
• rs1064797186
• NM_005249.5:c.685A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM6 PP3 PM2_Supporting PM1

This summary comes from the ClinGen Evidence Repository: The p.Ile229Leu variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID 18571142, 28661489) (PM1). The p.Ile229Leu variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with intellectual disability and seizures (Genetic Services Laboratory, University of Chicago internal data)(PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance (PP3). The p.Ile229Leu variant in FOXG1 is absent in gnomAD (PM2_supporting). In summary, the p.Ile229Leu variant in FOXG1 is classified as likely pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PM1, PM6, PP3, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16621657/MONDO:0100040/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 7.39

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 Likely_pathogenic. Variant got 6 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.685A>C	p.Ile229Leu	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.685A>C	p.Ile229Leu	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.685A>C	p.Ile229Leu	missense_variant	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1951A>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

FOXG1 disorder Pathogenic:1

Feb 18, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Ile229Leu variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID 18571142, 28661489) (PM1). The p.Ile229Leu variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with intellectual disability and seizures (Genetic Services Laboratory, University of Chicago internal data)(PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance (PP3). The p.Ile229Leu variant in FOXG1 is absent in gnomAD (PM2_supporting). In summary, the p.Ile229Leu variant in FOXG1 is classified as likely pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PM1, PM6, PP3, PM2_supporting). -

Rett syndrome, congenital variant Pathogenic:1

Aug 09, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.79		Gain of catalytic residue at N232 (P = 0.0168);
MVP		0.99
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.95
gMVP		1.0

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: rs1064797186; hg19: chr14-29237170;