14-28767417-GCACCACCACCACCAC-GCACCACCACCACCACCACCACCAC

Position:

• chr14-28767417-GCACCACCACCACCAC-GCACCACCACCACCACCACCACCAC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005249.5(FOXG1):​c.153_161dupCCACCACCA​(p.His52_His54dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 0.512

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.153_161dupCCACCACCA	p.His52_His54dup	disruptive_inframe_insertion	1/1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.153_161dupCCACCACCA	p.His52_His54dup	disruptive_inframe_insertion	1/1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.153_161dupCCACCACCA	p.His52_His54dup	disruptive_inframe_insertion	2/2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1419_374+1427dupCCACCACCA		intron_variant

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1242524 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 615224

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2021

Not observed in large population cohorts (Lek et al., 2016); In-frame insertion of 3 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

FOXG1 disorder Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 26, 2021

The p.His55_His57dup variant in FOXG1 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with clinical features of FOXG1 disorder (internal database, GeneDx) (PM6). The p.His55_His57dup variant in FOXG1 is absent in gnomAD (PM2_supporting). The p.His55_His57dup variant is an in-frame deletion/duplication present in a repetitive region of FOXG1 (BP3). In summary, the p.His55_His57dup variant in FOXG1 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM6, PM2_supporting, BP3). -

Rett syndrome, congenital variant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 31, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1162244). This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.153_161dup, results in the insertion of 3 amino acid(s) of the FOXG1 protein (p.His55_His57dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-29236623;