14-28767780-G-T

Variant names:

• chr14-28767780-G-T
• rs773297334
• NM_005249.5:c.501G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005249.5(FOXG1):​c.501G>T​(p.Glu167Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E167E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19882414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.501G>T	p.Glu167Asp	missense_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.501G>T	p.Glu167Asp	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.501G>T	p.Glu167Asp	missense_variant	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1767G>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000430 AC: 1 AN: 232292 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000138 AC: 2 AN: 1450144 Hom.: 0 Cov.: 36 AF XY: 0.00000139 AC XY: 1 AN XY: 721086

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.0000226 AC: 1 AN: 44338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110092

Other (OTH) AF: 0.00 AC: 0 AN: 60140

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome, congenital variant Uncertain:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 167 of the FOXG1 protein (p.Glu167Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.27	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.17
Sift	Benign	0.12	T
Sift4G	Benign	0.34	T
Polyphen		0.17	B
Vest4		0.099
MutPred		0.27		Gain of catalytic residue at K164 (P = 0.1123);
MVP		0.36
ClinPred		0.15	T
GERP RS		2.2
Varity_R		0.13
gMVP		0.49
Mutation Taster		=92/8	polymorphism

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: rs773297334; hg19: chr14-29236986;