14-28767750-G-T

Variant names:

• chr14-28767750-G-T
• rs398124205
• NM_005249.5:c.471G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2 BP4

This summary comes from the ClinGen Evidence Repository: The p.Lys157Asn variant in FOXG1 is present in 2 individuals in gnomAD (0.001%) (not sufficient to meet BS1 criteria). The p.Lys157Asn variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Lys157Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Lys157Asn variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA222858/MONDO:0100040/016

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: 3.18
• Publications: 0 publications found

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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005249.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.471G>T	p.Lys157Asn	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.471G>T	p.Lys157Asn	missense	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.471G>T	p.Lys157Asn	missense	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1737G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000644 AC: 1 AN: 155318 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000430 AC: 6 AN: 1395712 Hom.: 0 Cov.: 35 AF XY: 0.00000290 AC XY: 2 AN XY: 689424

African (AFR) AF: 0.00 AC: 0 AN: 32418

American (AMR) AF: 0.00 AC: 0 AN: 37344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 37174

South Asian (SAS) AF: 0.00 AC: 0 AN: 80242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4220

European-Non Finnish (NFE) AF: 0.00000553 AC: 6 AN: 1085290

Other (OTH) AF: 0.00 AC: 0 AN: 58226

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1

Oct 08, 2012

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rett syndrome, congenital variant Uncertain:1

Aug 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with FOXG1-related disease. ClinVar contains an entry for this variant (Variation ID: 95269). This sequence change replaces lysine with asparagine at codon 157 of the FOXG1 protein (p.Lys157Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine.

FOXG1 disorder Benign:1

Sep 01, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The p.Lys157Asn variant in FOXG1 is present in 2 individuals in gnomAD (0.001%) (not sufficient to meet BS1 criteria). The p.Lys157Asn variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Lys157Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Lys157Asn variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4).

Intellectual disability Benign:1

Jan 01, 2017

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.2
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.014
Sift	Benign	0.042	D
Sift4G	Benign	0.36	T
Polyphen		0.099	B
Vest4		0.29
MutPred		0.32		Loss of ubiquitination at K157 (P = 0.0063)
MVP		0.076
ClinPred		0.21	T
GERP RS		-0.25
Varity_R		0.079
gMVP		0.69
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs398124205; hg19: chr14-29236956;