rs267606826

Variant names:

• chr14-28767903-C-A
• rs267606826
• NM_005249.5:c.624C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-28767903-C-A
• chr14-28767903-C-G
• chr14-28767903-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005249.5(FOXG1):​c.624C>A​(p.Tyr208*) 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:4
• 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

Our verdict: Pathogenic. The variant received 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 144 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-28767903-C-A is Pathogenic according to our data. Variant chr14-28767903-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 453289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.624C>A	p.Tyr208*	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.624C>A	p.Tyr208*	stop_gained	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.624C>A	p.Tyr208*	stop_gained	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1890C>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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:3

Aug 05, 2016

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This terminating amino acid change (p.Y208X) has been reported in at least one affected individual (PMID 19578037). -

Mar 05, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the FOXG1 gene (p.Tyr208*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 282 amino acids of the FOXG1 protein. This variant is not present in population databases (ExAC no frequency). This nonsense change has been observed in individual(s) with clinical features of Rett syndrome (PMID: 28661489, 19578037). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 453289). For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Abnormal optic nerve morphology;C0038273:Stereotypic movement disorder;C0038379:Strabismus;C0557874:Global developmental delay;C1853743:Axial hypotonia Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.69	D
Vest4		0.88
GERP RS		-0.24
Mutation Taster		=0/200	disease causing (ClinVar)

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;