rs796052462

chr14-28767840-C-Achr14-28767840-C-G

Variant summary

Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_005249.5(FOXG1):c.561C>A(p.Asn187Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N187D) has been classified as Pathogenic.

• 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:19828): (long intergenic non-protein coding RNA 1551)

ACMG classification

Verdict is Pathogenic. Variant got 25 ACMG points.

• PS1: Transcript NM_005249.5 (FOXG1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 265363
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_005249.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-28767838-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1320045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, FOXG1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 14-28767840-C-A is Pathogenic according to our data. Variant chr14-28767840-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 205485.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-28767840-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXG1	ENST00000313071.7	c.561C>A	p.Asn187Lys	missense_variant	1/1		NM_005249.5	P1
FOXG1	ENST00000706482.1	c.561C>A	p.Asn187Lys	missense_variant	2/2			P1
LINC01551	ENST00000675861.1	n.374+1827C>A		intron_variant, non_coding_transcript_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
MutationTaster	Benign	1.0	D;D
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;