rs797045583

Positions:

• chr14-28767709-G-A
• chr14-28767709-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005249.5(FOXG1):​c.430G>A​(p.Glu144Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.21

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FOXG1. . Trascript score misZ 3.7891 (greater than threshold 3.09). GenCC has associacion of gene with Rett syndrome, congenital variant, FOXG1 disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23763192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.430G>A	p.Glu144Lys	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.430G>A	p.Glu144Lys	missense_variant	1/1		NM_005249.5	ENSP00000339004	P1
FOXG1	ENST00000706482.1	c.430G>A	p.Glu144Lys	missense_variant	2/2			ENSP00000516406	P1
LINC01551	ENST00000675861.1	n.374+1696G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 21, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2017

A variant of uncertain significance has been identified in the FOXG1 gene. The E144K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E144K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E144K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species and it does not occur within the forkhead binding domain where all previously reported missense variants in FOXG1 have been identified. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Rett syndrome, congenital variant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.0098
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.14	T
Polyphen		0.84	P
Vest4		0.20
MutPred		0.31		Gain of glycosylation at E144 (P = 0.0162);
MVP		0.16
ClinPred		0.88	D
GERP RS		2.9
Varity_R		0.28
gMVP		0.41

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: rs797045583; hg19: chr14-29236915;