14-28767488-A-C

Variant names:

• chr14-28767488-A-C
• rs587783633
• NM_005249.5:c.209A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BA1 BS2

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Gln70Pro variant in FOXG1 in gnomAD v4.1 is 0.00033 in the Admixed American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Gln70Pro variant is observed in at least 2 unaffected individuals (Internal database - Ambry) (BS2). Computational analysis prediction tools suggest that the p.Gln70Pro variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gln70Pro variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294776/MONDO:0100040/035

• Frequency:
  • Genomes: 𝑓 0.00026 (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:7
• Conservation: PhyloP100: 0.693
• Publications: 5 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 -13 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.
• BA1: 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.209A>C	p.Gln70Pro	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.209A>C	p.Gln70Pro	missense	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.209A>C	p.Gln70Pro	missense	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1475A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000272 AC: 38 AN: 139852 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000773

Gnomad ASJ AF: 0.000307

Gnomad EAS AF: 0.000846

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00370

Gnomad NFE AF: 0.000219

Gnomad OTH AF: 0.00157

GnomAD2 exomes AF: 0.000138 AC: 5 AN: 36220 AF XY: 0.000178

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: 0.000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 132 AN: 871366 Hom.: 0 Cov.: 16 AF XY: 0.000141 AC XY: 59 AN XY: 418988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000304 AC: 5 AN: 16426

American (AMR) AF: 0.00 AC: 0 AN: 6786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9474

East Asian (EAS) AF: 0.0000950 AC: 1 AN: 10530

South Asian (SAS) AF: 0.000195 AC: 5 AN: 25696

European-Finnish (FIN) AF: 0.0000827 AC: 1 AN: 12086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1988

European-Non Finnish (NFE) AF: 0.000152 AC: 115 AN: 757940

Other (OTH) AF: 0.000164 AC: 5 AN: 30440

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000264 AC: 37 AN: 139948 Hom.: 0 Cov.: 31 AF XY: 0.000206 AC XY: 14 AN XY: 68106

African (AFR) AF: 0.0000779 AC: 3 AN: 38504

American (AMR) AF: 0.000772 AC: 11 AN: 14252

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 1 AN: 3258

East Asian (EAS) AF: 0.000849 AC: 4 AN: 4712

South Asian (SAS) AF: 0.000224 AC: 1 AN: 4470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 246

European-Non Finnish (NFE) AF: 0.000219 AC: 14 AN: 63796

Other (OTH) AF: 0.00155 AC: 3 AN: 1932

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000366

ExAC AF: 0.0000714 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	Rett syndrome, congenital variant (2)
-	-	1	FOXG1 disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (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	-0.61
CADD	Benign	16
DANN	Benign	0.78
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.69
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.035
Sift	Benign	0.35	T
Sift4G	Benign	0.29	T
Polyphen		0.80	P
Vest4		0.33
MutPred		0.32		Gain of catalytic residue at P65 (P = 5e-04)
MVP		0.040
ClinPred		0.041	T
GERP RS		0.93
Varity_R		0.089
gMVP		0.16
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: rs587783633; hg19: chr14-29236694;