14-28767782-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_005249.5(FOXG1):c.503G>T(p.Gly168Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,603,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G168A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.88

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 0 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=0.23890877).
• BP6: Variant 14-28767782-G-T is Benign according to our data. Variant chr14-28767782-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205483.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5	c.503G>T	p.Gly168Val	missense_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXG1	ENST00000313071.7	c.503G>T	p.Gly168Val	missense_variant	1/1		NM_005249.5	P1
FOXG1	ENST00000706482.1	c.503G>T	p.Gly168Val	missense_variant	2/2			P1
LINC01551	ENST00000675861.1	n.374+1769G>T		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000216

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2013

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2018

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 v4.3

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
MutationTaster	Benign	1.0	D;D
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

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: rs148157138; hg19: chr14-29236988;