rs138747073

Variant names:

• chr14-28768479-C-A
• rs138747073
• NM_005249.5:c.1200C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-28768479-C-A
• chr14-28768479-C-G
• chr14-28768479-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005249.5(FOXG1):​c.1200C>A​(p.Tyr400*) 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, single submitter P:2
• Conservation: PhyloP100: 1.58

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 Likely_pathogenic. Variant got 8 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 0.184 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-28768479-C-A is Pathogenic according to our data. Variant chr14-28768479-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 189608.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-28768479-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.1200C>A	p.Tyr400*	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.1200C>A	p.Tyr400*	stop_gained	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.1200C>A	p.Tyr400*	stop_gained	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+2466C>A		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:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 12, 2013

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

truncation mutation causing reduction in chromatin binding affinity (in vitro assay) -

FOXG1 disorder Pathogenic:1

May 27, 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 has been identified as a de novo occurrence in an individual with FOXG1 disorder without confirmation of paternity and maternity (PM6, PMID: 22091895). This variant is absent from gnomAD v4.1 (PM2_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.76	D
Vest4		0.87
GERP RS		3.2

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: rs138747073; hg19: chr14-29237685;