rs796052462

Positions:

• chr14-28767840-C-A
• chr14-28767840-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS2 PS4 PM2_Supporting PM1

This summary comes from the ClinGen Evidence Repository: The p.Asn187Lys variant in FOXG1 has been reported as a de novo occurrence (biological parenthood confirmed) in at least 2 individuals with FOXG1 disorder (PMID 26795593, 28661489) (PS2_very strong). The p.Asn187Lys variant in FOXG1 has been observed in at least 5 other individuals with FOXG1 disorder (PMID 26795593, 25356970, 28661489) (PS4). This variant occurs in the well-characterized Forkhead functional domain of the FOXG1 (PM1). The p.Asn187Lys variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Asn187Lys variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PS2_very strong, PS4, PM1, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA204685/MONDO:0100040/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 4.81

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:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS2: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.561C>A	p.Asn187Lys	missense_variant	1/1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.561C>A	p.Asn187Lys	missense_variant	1/1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.561C>A	p.Asn187Lys	missense_variant	2/2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1827C>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2013

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2016

The Asn187Lys missense change has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Asn187Lys in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as an uncharged Asparagine residue is replaced by a positively charged Lysine residue. It alters a conserved position in the forkhead binding domain where all previously reported missense variant in FOXG1 have been identified. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Asn187Lys is a disease-causing variant or a rare benign variant. -

FOXG1 disorder Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 25, 2021

The p.Asn187Lys variant in FOXG1 has been reported as a de novo occurrence (biological parenthood confirmed) in at least 2 individuals with FOXG1 disorder (PMID 26795593, 28661489) (PS2_very strong). The p.Asn187Lys variant in FOXG1 has been observed in at least 5 other individuals with FOXG1 disorder (PMID 26795593, 25356970, 28661489) (PS4). This variant occurs in the well-characterized Forkhead functional domain of the FOXG1 (PM1). The p.Asn187Lys variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Asn187Lys variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PS2_very strong, PS4, PM1, PM2_supporting). -

Rett syndrome, congenital variant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.66		Gain of catalytic residue at P182 (P = 2e-04);
MVP		0.97
ClinPred		1.0	D
GERP RS		1.8
Varity_R		0.91
gMVP		0.99

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: rs796052462; hg19: chr14-29237046;