14-28767782-G-T

Variant names:

• chr14-28767782-G-T
• rs148157138
• NM_005249.5:c.503G>T

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Gly168Val variant in FOXG1 in gnomAD v4.1 is 0.000018 in the European (Finnish) population (not sufficient to meet BS1 criteria). The p.Gly168Val variant is observed in at least 1 unaffected individual (Internal database - Ambry) (BS2_Supporting). Computational prediction analysis tools are inconclusive for this variant (no criteria met). In summary, the p.Gly168Val variant in FOXG1 is classified as a variant of unknown significance based on the ACMG/AMP criteria (BS2_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314606/MONDO:0100040/035

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 3.88
• Publications: 1 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 -1 ACMG points.

• BS2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.503G>T	p.Gly168Val	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.503G>T	p.Gly168Val	missense	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.503G>T	p.Gly168Val	missense	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1769G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451572 Hom.: 0 Cov.: 35 AF XY: 0.00000277 AC XY: 2 AN XY: 721954

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85748

European-Finnish (FIN) AF: 0.0000216 AC: 1 AN: 46190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110510

Other (OTH) AF: 0.0000166 AC: 1 AN: 60186

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74220

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

FOXG1 disorder Uncertain:1

Jun 25, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The highest population minor allele frequency of the p.Gly168Val variant in FOXG1 in gnomAD v4.1 is 0.000018 in the European (Finnish) population (not sufficient to meet BS1 criteria). The p.Gly168Val variant is observed in at least 1 unaffected individual (Internal database - Ambry) (BS2_Supporting). Computational prediction analysis tools are inconclusive for this variant (no criteria met). In summary, the p.Gly168Val variant in FOXG1 is classified as a variant of unknown significance based on the ACMG/AMP criteria (BS2_Supporting).

not provided Uncertain:1

Apr 15, 2013

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly168Val (GGG>GTG): c.503 G>T in exon 1 of the FOXG1 gene (NM_005249.3). The Gly168Val missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is conservative as both Glycine and Valine are uncharged, non-polar amino acid residues. Gly168Val alters a position that is not conserved through evolution, and it does not occur within the forkhead binding domain where all previously reported missense mutations in FOXG1 have been identified, to our knowledge. Several in-silico algorithms predict Gly168Val is non-pathogenic, although one model predicts it may be damaging to the structure/function of the protein. Therefore, based on the currently available information, it is unclear whether Gly168Val is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).

Inborn genetic diseases Benign:1

Jan 24, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Uncertain	0.010	D
Sift4G	Benign	0.11	T
Polyphen		0.11	B
Vest4		0.14
MutPred		0.28		Loss of relative solvent accessibility (P = 0.0404)
MVP		0.82
ClinPred		0.64	D
GERP RS		0.91
Varity_R		0.14
gMVP		0.62
Mutation Taster		=91/9	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: rs148157138; hg19: chr14-29236988;