rs786204999

Variant names:

• chr14-28768527-C-G
• rs786204999
• NM_005249.5:c.1248C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-28768527-C-G
• chr14-28768527-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_005249.5(FOXG1):​c.1248C>G​(p.Tyr416*) 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 (★★).

• 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: 3.23

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 14 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. Fraction of 0.151 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-28768527-C-G is Pathogenic according to our data. Variant chr14-28768527-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 189609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-28768527-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.1248C>G	p.Tyr416*	stop_gained	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.1248C>G	p.Tyr416*	stop_gained	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.1248C>G	p.Tyr416*	stop_gained	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+2514C>G		intron_variant	Intron 1 of 3

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

Jan 20, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2021

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2010

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Pathogenic:1

Aug 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21488007, 28661489, 23632790, 25565401, 32757993, 19806373) -

FOXG1 disorder Pathogenic:1

May 10, 2024

Centre for Population Genomics, CPG

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with FOXG1 disorder (PS4_Supporting).PMID:23632790 PMID:19806373 PMID:28661489 Variation ID: 189609 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.87
GERP RS		4.1

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: rs786204999; hg19: chr14-29237733;