NM_005249.5:c.218A>C

Variant names:

• chr14-28767497-A-C
• rs760663911
• NM_005249.5:c.218A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BS1 BP5_Strong BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Gln73Pro variant in FOXG1 is 0.027% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gln73Pro variant is observed in at least 50 unaffected individuals (internal database - GeneDx) (BS2). The p.Gln73Pro variant is found in at least 8 individuals with an alternate molecular basis of disease (internal database - Invitae, internal database - GeneDx) (BP5_Strong). Computational analysis prediction tools suggest that the p.Gln73Pro variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gln73Pro variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_Strong, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA238810/MONDO:0100040/035

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:4
• Conservation: PhyloP100: -0.795
• 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

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• 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.218A>C	p.Gln73Pro	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.218A>C	p.Gln73Pro	missense	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.218A>C	p.Gln73Pro	missense	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1484A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000179 AC: 25 AN: 139878 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00107 AC: 5 AN: 4690 AF XY: 0.000970

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00355

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000286 AC: 24 AN: 838472 Hom.: 0 Cov.: 16 AF XY: 0.0000251 AC XY: 10 AN XY: 398102

African (AFR) AF: 0.0000639 AC: 1 AN: 15642

American (AMR) AF: 0.00 AC: 0 AN: 2946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6302

East Asian (EAS) AF: 0.00 AC: 0 AN: 8342

South Asian (SAS) AF: 0.0000552 AC: 1 AN: 18110

European-Finnish (FIN) AF: 0.000125 AC: 1 AN: 7998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1824

European-Non Finnish (NFE) AF: 0.0000254 AC: 19 AN: 748512

Other (OTH) AF: 0.0000695 AC: 2 AN: 28796

GnomAD4 genome AF: 0.000179 AC: 25 AN: 139974 Hom.: 0 Cov.: 31 AF XY: 0.000206 AC XY: 14 AN XY: 68104

African (AFR) AF: 0.000207 AC: 8 AN: 38692

American (AMR) AF: 0.000281 AC: 4 AN: 14246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3276

East Asian (EAS) AF: 0.000213 AC: 1 AN: 4684

South Asian (SAS) AF: 0.00 AC: 0 AN: 4426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.000188 AC: 12 AN: 63682

Other (OTH) AF: 0.00 AC: 0 AN: 1920

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.000102 AC: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	FOXG1 disorder (3)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.80
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.049
Sift	Benign	0.62	T
Sift4G	Benign	0.24	T
Polyphen		0.90	P
Vest4		0.16
MutPred		0.36		Gain of catalytic residue at Q73 (P = 5e-04)
MVP		0.055
ClinPred		0.039	T
GERP RS		0.93
Varity_R		0.26
gMVP		0.12
Mutation Taster		=87/13	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: rs760663911; hg19: chr14-29236703; COSMIC: COSV100486810; COSMIC: COSV100486810;