rs781726187

chr14-28767722-G-Achr14-28767722-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005249.5(FOXG1):c.443G>A(p.Gly148Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,377,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G148V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FOXG1
• BP4: Computational evidence support a benign effect (MetaRNN=0.30519757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5	c.443G>A	p.Gly148Asp	missense_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXG1	ENST00000313071.7	c.443G>A	p.Gly148Asp	missense_variant	1/1		NM_005249.5	P1
FOXG1	ENST00000706482.1	c.443G>A	p.Gly148Asp	missense_variant	2/2			P1
LINC01551	ENST00000675861.1	n.374+1709G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000154 AC: 2 AN: 129680 Hom.: 0 AF XY: 0.0000141 AC XY: 1 AN XY: 70940

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000821

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1377242 Hom.: 0 Cov.: 33 AF XY: 0.00000295 AC XY: 2 AN XY: 678666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000843

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome, congenital variant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 21, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FOXG1 protein function. ClinVar contains an entry for this variant (Variation ID: 572556). This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 148 of the FOXG1 protein (p.Gly148Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.088
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.94	N;N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	0.89	N
REVEL	Benign	0.10
Sift	Benign	0.062	T
Sift4G	Benign	0.78	T
Polyphen		1.0	D
Vest4		0.16
MutPred		0.27		Gain of catalytic residue at A151 (P = 0.0194);
MVP		0.20
ClinPred		0.29	T
GERP RS		2.9
Varity_R		0.12
gMVP		0.50

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: rs781726187; hg19: chr14-29236928;