rs760663911

Positions:

• chr14-28767497-A-C
• chr14-28767497-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2 BP4 BS1 BP5_Strong

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

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:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.218A>C	p.Gln73Pro	missense_variant	1/1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.218A>C	p.Gln73Pro	missense_variant	1/1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.218A>C	p.Gln73Pro	missense_variant	2/2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1484A>C		intron_variant

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

GnomAD3 exomes AF: 0.00107 AC: 5 AN: 4690 Hom.: 0 AF XY: 0.000970 AC XY: 3 AN XY: 3094

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 SAS exome AF: 0.000818

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

Gnomad4 AFR exome AF: 0.0000639

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000552

Gnomad4 FIN exome AF: 0.000125

Gnomad4 NFE exome AF: 0.0000254

Gnomad4 OTH exome AF: 0.0000695

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

Gnomad4 AFR AF: 0.000207

Gnomad4 AMR AF: 0.000281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000213

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.000102 AC: 1

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	- -

Rett syndrome, congenital variant Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 07, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

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

Oct 13, 2023

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). -

Computational scores

Source: dbNSFP v4.3

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
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

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: rs760663911; hg19: chr14-29236703; COSMIC: COSV100486810; COSMIC: COSV100486810;