rs375378714

chr14-28767768-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005249.5(FOXG1):c.489C>T(p.Gly163=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,565,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (0 hom.)
• Consequence: FOXG1 NM_005249.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 1.60

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 14-28767768-C-T is Benign according to our data. Variant chr14-28767768-C-T is described in ClinVar as [Benign]. Clinvar id is 137390.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-28767768-C-T is described in Lovd as [Likely_benign]. Variant chr14-28767768-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000578 (87/150532) while in subpopulation NFE AF= 0.00102 (69/67578). AF 95% confidence interval is 0.000827. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5	c.489C>T	p.Gly163=	synonymous_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXG1	ENST00000313071.7	c.489C>T	p.Gly163=	synonymous_variant	1/1		NM_005249.5	P1
FOXG1	ENST00000706482.1	c.489C>T	p.Gly163=	synonymous_variant	2/2			P1
LINC01551	ENST00000675861.1	n.374+1755C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 87 AN: 150532 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000596

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000973

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00102

Gnomad OTH AF: 0.000486

GnomAD3 exomes AF: 0.000484 AC: 101 AN: 208658 Hom.: 0 AF XY: 0.000540 AC XY: 62 AN XY: 114838

Gnomad AFR exome AF: 0.000165

Gnomad AMR exome AF: 0.000375

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000359

Gnomad FIN exome AF: 0.000159

Gnomad NFE exome AF: 0.000825

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000741 AC: 1049 AN: 1414872 Hom.: 0 Cov.: 37 AF XY: 0.000772 AC XY: 542 AN XY: 701940

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.000444

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000598

Gnomad4 FIN exome AF: 0.0000981

Gnomad4 NFE exome AF: 0.000903

Gnomad4 OTH exome AF: 0.000544

GnomAD4 genome AF: 0.000578 AC: 87 AN: 150532 Hom.: 0 Cov.: 32 AF XY: 0.000626 AC XY: 46 AN XY: 73444

Gnomad4 AFR AF: 0.000171

Gnomad4 AMR AF: 0.000596

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000973

Gnomad4 NFE AF: 0.00102

Gnomad4 OTH AF: 0.000486

Alfa AF: 0.000763 Hom.: 0

Bravo AF: 0.000525

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FOXG1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 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

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 26, 2021

The allele frequency of the p.Gly163= variant in FOXG1 is 0.09% in European (Non-Finnish) sub population in gnomAD, 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). The p.Gly163= variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Gly163= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP5). -

FOXG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2020

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). -

Rett syndrome, congenital variant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	14
Dann	Uncertain	0.98

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: rs375378714; hg19: chr14-29236974;