14-28767497-AGCCGCCGCC-AGCCGCCGCCGCC

Variant names:

• chr14-28767497-A-AGCC
• rs786200975
• NM_005249.5:c.234_236dupGCC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_005249.5(FOXG1):​c.234_236dupGCC​(p.Pro79dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 978,456 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 2.33
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005249.5
• BP6: Variant 14-28767497-A-AGCC is Benign according to our data. Variant chr14-28767497-A-AGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 167090.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00246 (344/139972) while in subpopulation AFR AF = 0.00809 (313/38690). AF 95% confidence interval is 0.00735. There are 1 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 344 AD gene.

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.234_236dupGCC	p.Pro79dup	disruptive_inframe_insertion	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.234_236dupGCC	p.Pro79dup	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.234_236dupGCC	p.Pro79dup	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1500_374+1502dupGCC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 344 AN: 139876 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00134

Gnomad ASJ AF: 0.000305

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000942

Gnomad OTH AF: 0.00263

GnomAD2 exomes AF: 0.00 AC: 0 AN: 4690 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000157 AC: 132 AN: 838484 Hom.: 0 Cov.: 15 AF XY: 0.000133 AC XY: 53 AN XY: 398108

African (AFR) AF: 0.00409 AC: 64 AN: 15638

American (AMR) AF: 0.000678 AC: 2 AN: 2948

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 1 AN: 6304

East Asian (EAS) AF: 0.00 AC: 0 AN: 8344

South Asian (SAS) AF: 0.00 AC: 0 AN: 18110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8000

Middle Eastern (MID) AF: 0.00110 AC: 2 AN: 1824

European-Non Finnish (NFE) AF: 0.0000721 AC: 54 AN: 748518

Other (OTH) AF: 0.000313 AC: 9 AN: 28798

GnomAD4 genome AF: 0.00246 AC: 344 AN: 139972 Hom.: 1 Cov.: 31 AF XY: 0.00232 AC XY: 158 AN XY: 68104

African (AFR) AF: 0.00809 AC: 313 AN: 38690

American (AMR) AF: 0.00133 AC: 19 AN: 14246

Ashkenazi Jewish (ASJ) AF: 0.000305 AC: 1 AN: 3276

East Asian (EAS) AF: 0.00 AC: 0 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: 0.0000942 AC: 6 AN: 63682

Other (OTH) AF: 0.00260 AC: 5 AN: 1920

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=78/22	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786200975; hg19: chr14-29236703;