14-28767471-ACCGCCGCCGCCGCCGCAGCAGCAGCAG-ACCGCCGCCGCCGCCGCAGCAGCAGCAGCCGCCGCCGCCGCCGCAGCAGCAGCAG

Position:

chr14-28767471-ACCGCCGCCGCCGCCGCAGCAGCAGCAG-ACCGCCGCCGCCGCCGCAGCAGCAGCAGCCGCCGCCGCCGCCGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_005249.5(FOXG1):c.209_235dupAGCAGCAGCAGCCGCCGCCGCCGCCGC(p.Gln70_Pro78dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 128,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXG1
NM_005249.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:3

Conservation

PhyloP100: 1.26

Variant links:

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]

FOXG1 links:

LINC01551 (HGNC:):

LINC01551 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 14-28767471-A-ACCGCCGCCGCCGCCGCAGCAGCAGCAG is Benign according to our data. Variant chr14-28767471-A-ACCGCCGCCGCCGCCGCAGCAGCAGCAG is described in ClinVar as [Benign]. Clinvar id is 421833.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000357 (46/128986) while in subpopulation AFR AF= 0.00121 (42/34820). AF 95% confidence interval is 0.000916. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5 linkuse as main transcript	c.209_235dupAGCAGCAGCAGCCGCCGCCGCCGCCGC	p.Gln70_Pro78dup	disruptive_inframe_insertion	1/1	ENST00000313071.7	NP_005240.3	P55316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FOXG1	ENST00000313071.7 linkuse as main transcript	c.209_235dupAGCAGCAGCAGCCGCCGCCGCCGCCGC	p.Gln70_Pro78dup	disruptive_inframe_insertion	1/1	6	NM_005249.5	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1 linkuse as main transcript	c.209_235dupAGCAGCAGCAGCCGCCGCCGCCGCCGC	p.Gln70_Pro78dup	disruptive_inframe_insertion	2/2			ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1 linkuse as main transcript	n.374+1475_374+1501dupAGCAGCAGCAGCCGCCGCCGCCGCCGC		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000357

AC:

AN:

128904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000152

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00113

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000104

AC:

AN:

962094

Hom.:

Cov.:

AF XY:

0.0000128

AC XY:

AN XY:

467336

show subpopulations

Gnomad4 AFR exome

AF:

0.000460

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000261

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000357

AC:

AN:

128986

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

AN XY:

62816

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.000151

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00112

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2018

The c.209_235dup27 variant (also known as p.Q70_P78dup), located in coding exon 1 of the FOXG1 gene, results from an in-frame duplication of 27 nucleotides at nucleotide positions 209 to 235. This results in the duplication of 9 extra residues (QQQQPPPPP) between codons 70 and 78. This variant did not co-segregate with disease in one individual tested in our laboratory. These amino acid positions are not conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2021

- -

FOXG1 disorder

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Dec 06, 2023

The allele frequency of the p.Gln70_Pro78dup variant in FOXG1 is 0.09% in the African sub population in gnomAD v4, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). This variant was observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). Additionally, the p.Gln70_Pro78dup variant is an in-frame duplication present in a repetitive region of FOXG1 (BP3). In summary, the p.Gln70_Pro78dup variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2_supporting, BP3). -

Rett syndrome, congenital variant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over