rs796052455

Variant names:

• chr14-28767655-G-A
• rs796052455
• NM_005249.5:c.376G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS1 BP5_Strong BS2

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Gly126Ser variant in FOXG1 in gnomAD v4.1 is 0.0001782 in European (non-Finnish) population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Gly126Ser variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Gly126Ser variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). In summary, the p.Gly126Ser variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314582/MONDO:0100040/035

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 1.92
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.376G>A	p.Gly126Ser	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.376G>A	p.Gly126Ser	missense	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.376G>A	p.Gly126Ser	missense	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1642G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000726 AC: 11 AN: 151430 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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000525 AC: 4 AN: 76180 AF XY: 0.0000760

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: 0.000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 200 AN: 1318346 Hom.: 0 Cov.: 33 AF XY: 0.000138 AC XY: 89 AN XY: 644244

African (AFR) AF: 0.0000338 AC: 1 AN: 29586

American (AMR) AF: 0.0000368 AC: 1 AN: 27186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20290

East Asian (EAS) AF: 0.00 AC: 0 AN: 35288

South Asian (SAS) AF: 0.00 AC: 0 AN: 67606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3718

European-Non Finnish (NFE) AF: 0.000180 AC: 189 AN: 1049292

Other (OTH) AF: 0.000164 AC: 9 AN: 54830

GnomAD4 genome AF: 0.0000660 AC: 10 AN: 151524 Hom.: 0 Cov.: 31 AF XY: 0.0000405 AC XY: 3 AN XY: 74044

African (AFR) AF: 0.00 AC: 0 AN: 41506

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67718

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	FOXG1 disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Rett syndrome, congenital variant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.69	N
REVEL	Benign	0.024
Sift	Benign	0.23	T
Sift4G	Benign	0.68	T
Polyphen		0.018	B
Vest4		0.062
MVP		0.061
ClinPred		0.044	T
GERP RS		1.9
Varity_R		0.089
gMVP		0.22
Mutation Taster		=95/5	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: rs796052455; hg19: chr14-29236861;