14-28767903-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005249.5(FOXG1):c.624C>G(p.Tyr208Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y208Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.712

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 141 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-28767903-C-G is Pathogenic according to our data. Variant chr14-28767903-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-28767903-C-G is described in Lovd as [Pathogenic]. Variant chr14-28767903-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5	c.624C>G	p.Tyr208Ter	stop_gained	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXG1	ENST00000313071.7	c.624C>G	p.Tyr208Ter	stop_gained	1/1		NM_005249.5	P1
FOXG1	ENST00000706482.1	c.624C>G	p.Tyr208Ter	stop_gained	2/2			P1
LINC01551	ENST00000675861.1	n.374+1890C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 20, 2018	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2018

The p.Y208* pathogenic mutation (also known as c.624C>G), located in coding exon 1 of the FOXG1 gene, results from a C to G substitution at nucleotide position 624. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This alteration has been detected twice in the literature, once as a de novo occurrence in a female with Rett syndrome (Mencarelli MA et al. J. Med. Genet., 2010 Jan;47:49-53) and once in a male with Rett syndrome features (Mitter D et al. Genet. Med., 2018 01;20:98-108). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2020

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21488007, 19578037, 28661489) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.71	D
MutationTaster	Benign	1.0	D;D
Vest4		0.88
GERP RS		-0.24

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: rs267606826; hg19: chr14-29237109;