NM_005249.5:c.561C>A

Variant names:

• chr14-28767840-C-A
• rs796052462
• NM_005249.5:c.561C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS2 PM2_Supporting PM1 PS4

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
• Publications: 6 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 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.

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.561C>A	p.Asn187Lys	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.561C>A	p.Asn187Lys	missense	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.561C>A	p.Asn187Lys	missense	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1827C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	FOXG1 disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	Rett syndrome, congenital variant (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.8
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
Mutation Taster		=0/100	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: rs796052462; hg19: chr14-29237046;