chr14-28767873-C-G

Variant names:

• chr14-28767873-C-G
• rs141088742
• NM_005249.5:c.594C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BA1 BP5_Strong BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro198= variant in FOXG1 is 0.04% in African sub population in gnomAD v2.1.1, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Pro198= variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Pro198= variant is found in at least 3 patients with an alternate molecular basis of disease (GeneDx internal database) (BP5_strong). The p.Pro198= variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene; however, as this is a synonymous change, there would be no affect on the amino acid sequence of the functional domain (PM1 not met). In summary, the p.Pro198= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314590/MONDO:0100040/035

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: FOXG1 NM_005249.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: -1.54
• Publications: 0 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 -16 ACMG points.

• BP5: 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.594C>G	p.Pro198Pro	synonymous	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.594C>G	p.Pro198Pro	synonymous	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.594C>G	p.Pro198Pro	synonymous	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1860C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 251050 AF XY: 0.0000957

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461824 Hom.: 0 Cov.: 34 AF XY: 0.0000715 AC XY: 52 AN XY: 727216

African (AFR) AF: 0.000329 AC: 11 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000836 AC: 93 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74440

African (AFR) AF: 0.000265 AC: 11 AN: 41570

American (AMR) AF: 0.000392 AC: 6 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000159

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	9.0
DANN	Benign	0.88
PhyloP100		-1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141088742; hg19: chr14-29237079;