NM_005249.5:c.256C>A

Variant names:

• chr14-28767535-C-A
• rs398124202
• NM_005249.5:c.256C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BS2 BP4

This summary comes from the ClinGen Evidence Repository: The p.Gln86Lys variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Gln86Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Gln86Lys variant in FOXG1 is absent from gnomAD (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: BS2, BP4 (approved 8/25/22). LINK:https://erepo.genome.network/evrepo/ui/classification/CA222854/MONDO:0100040/016

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 1.66
• Publications: 6 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

Specifications for FOXG1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.256C>A	p.Gln86Lys	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.256C>A	p.Gln86Lys	missense	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.256C>A	p.Gln86Lys	missense	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1522C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000678 AC: 1 AN: 147538 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000107 AC: 1 AN: 934236 Hom.: 0 Cov.: 18 AF XY: 0.00000227 AC XY: 1 AN XY: 439890

African (AFR) AF: 0.00 AC: 0 AN: 18282

American (AMR) AF: 0.00 AC: 0 AN: 4584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8942

East Asian (EAS) AF: 0.00 AC: 0 AN: 13432

South Asian (SAS) AF: 0.00 AC: 0 AN: 18162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2202

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 821688

Other (OTH) AF: 0.00 AC: 0 AN: 34020

GnomAD4 genome AF: 0.00000678 AC: 1 AN: 147538 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71806

African (AFR) AF: 0.00 AC: 0 AN: 40926

American (AMR) AF: 0.00 AC: 0 AN: 14828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66354

Other (OTH) AF: 0.00 AC: 0 AN: 2026

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	FOXG1 disorder (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.029
Sift	Benign	0.11	T
Sift4G	Benign	0.69	T
Polyphen		0.019	B
Vest4		0.10
MutPred		0.31		Gain of catalytic residue at P84 (P = 0.001)
MVP		0.18
ClinPred		0.088	T
GERP RS		2.0
Varity_R		0.14
gMVP		0.20
Mutation Taster		=97/3	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: rs398124202; hg19: chr14-29236741;