14-28767497-AGCCGCCGCC-AGCCGCCGCCGCC

Position:

• chr14-28767497-AGCCGCCGCC-AGCCGCCGCCGCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005249.5(FOXG1):​c.234_236dupGCC​(p.Pro79dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 978,456 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 2.33

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 14-28767497-A-AGCC is Benign according to our data. Variant chr14-28767497-A-AGCC is described in ClinVar as [Likely_benign]. Clinvar id is 167090.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00246 (344/139972) while in subpopulation AFR AF= 0.00809 (313/38690). AF 95% confidence interval is 0.00735. There are 1 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.234_236dupGCC	p.Pro79dup	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.234_236dupGCC	p.Pro79dup	disruptive_inframe_insertion	1/1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.234_236dupGCC	p.Pro79dup	disruptive_inframe_insertion	2/2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1500_374+1502dupGCC		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 344 AN: 139876 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00134

Gnomad ASJ AF: 0.000305

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000942

Gnomad OTH AF: 0.00263

GnomAD4 exome AF: 0.000157 AC: 132 AN: 838484 Hom.: 0 Cov.: 15 AF XY: 0.000133 AC XY: 53 AN XY: 398108

Gnomad4 AFR exome AF: 0.00409

Gnomad4 AMR exome AF: 0.000678

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000721

Gnomad4 OTH exome AF: 0.000313

GnomAD4 genome AF: 0.00246 AC: 344 AN: 139972 Hom.: 1 Cov.: 31 AF XY: 0.00232 AC XY: 158 AN XY: 68104

Gnomad4 AFR AF: 0.00809

Gnomad4 AMR AF: 0.00133

Gnomad4 ASJ AF: 0.000305

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000942

Gnomad4 OTH AF: 0.00260

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	FOXG1: BS1, BS2 -

Rett syndrome, congenital variant Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 03, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 22, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FOXG1 disorder Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Apr 17, 2023

The c.234_236dup (p.Pro79_Pro80insPro) variant is observed in at least 2 unaffected individuals (GeneDx internal database)(BS2). The c.234_236dup variant is an in-frame duplication present in a repetitive region of FOXG1 (BP3). The c.234_236dup variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). In summary, the c.234_236dup (p.Pro79_Pro80insPro) variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP3, BP5). -

FOXG1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786200975; hg19: chr14-29236703;