chr14-28767726-C-T

Variant names:

• chr14-28767726-C-T
• rs112803404
• NM_005249.5:c.447C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP7 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala149= variant in FOXG1 is 0.227% in European (Non-Finnish) sub population in gnomAD, 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 silent p.Ala149= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala149= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA232483/MONDO:0100040/016

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: FOXG1 NM_005249.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: -0.189
• 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 -9 ACMG points.

• BP7: 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.447C>T	p.Ala149Ala	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.447C>T	p.Ala149Ala	synonymous	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.447C>T	p.Ala149Ala	synonymous	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1713C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 150 AN: 149694 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000431

Gnomad FIN AF: 0.000392

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.00108 AC: 142 AN: 131114 AF XY: 0.00100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000368

Gnomad ASJ exome AF: 0.000381

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000357

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.00183 AC: 2504 AN: 1364848 Hom.: 7 Cov.: 34 AF XY: 0.00185 AC XY: 1247 AN XY: 672992

African (AFR) AF: 0.000128 AC: 4 AN: 31368

American (AMR) AF: 0.000449 AC: 16 AN: 35612

Ashkenazi Jewish (ASJ) AF: 0.000443 AC: 11 AN: 24818

East Asian (EAS) AF: 0.00 AC: 0 AN: 35664

South Asian (SAS) AF: 0.000356 AC: 28 AN: 78590

European-Finnish (FIN) AF: 0.000419 AC: 14 AN: 33444

Middle Eastern (MID) AF: 0.00124 AC: 5 AN: 4024

European-Non Finnish (NFE) AF: 0.00223 AC: 2370 AN: 1064270

Other (OTH) AF: 0.000981 AC: 56 AN: 57058

GnomAD4 genome AF: 0.00100 AC: 150 AN: 149804 Hom.: 1 Cov.: 32 AF XY: 0.000807 AC XY: 59 AN XY: 73140

African (AFR) AF: 0.000293 AC: 12 AN: 40994

American (AMR) AF: 0.000133 AC: 2 AN: 15064

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 4994

South Asian (SAS) AF: 0.000431 AC: 2 AN: 4638

European-Finnish (FIN) AF: 0.000392 AC: 4 AN: 10206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00190 AC: 128 AN: 67206

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.000963

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Rett syndrome, congenital variant (3)
-	-	2	not specified (2)
-	-	1	FOXG1 disorder (1)
-	-	1	FOXG1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.97
PhyloP100		-0.19
Mutation Taster		=100/0	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: rs112803404; hg19: chr14-29236932;