14-28767497-AGCCGCCGCC-AGCCGCC

Variant names:

• chr14-28767497-AGCC-A
• rs786200975
• NM_005249.5:c.234_236delGCC

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_005249.5(FOXG1):​c.234_236delGCC​(p.Pro79del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 975,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P78P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000057 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005249.5
• BP6: Variant 14-28767497-AGCC-A is Benign according to our data. Variant chr14-28767497-AGCC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 704508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 8 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_236delGCC	p.Pro79del	disruptive_inframe_deletion	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_236delGCC	p.Pro79del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.234_236delGCC	p.Pro79del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1500_374+1502delGCC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000572 AC: 8 AN: 139876 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000471

Gnomad OTH AF: 0.00

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: 0.000374 AC: 313 AN: 835846 Hom.: 0 AF XY: 0.000413 AC XY: 164 AN XY: 396838

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

African (AFR) AF: 0.000256 AC: 4 AN: 15598

American (AMR) AF: 0.00102 AC: 3 AN: 2940

Ashkenazi Jewish (ASJ) AF: 0.000636 AC: 4 AN: 6290

East Asian (EAS) AF: 0.000840 AC: 7 AN: 8330

South Asian (SAS) AF: 0.000111 AC: 2 AN: 18064

European-Finnish (FIN) AF: 0.000501 AC: 4 AN: 7984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1816

European-Non Finnish (NFE) AF: 0.000367 AC: 274 AN: 746120

Other (OTH) AF: 0.000523 AC: 15 AN: 28704

⚠️ 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: 0.0000572 AC: 8 AN: 139972 Hom.: 0 Cov.: 31 AF XY: 0.0000294 AC XY: 2 AN XY: 68102

African (AFR) AF: 0.0000775 AC: 3 AN: 38692

American (AMR) AF: 0.000140 AC: 2 AN: 14246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3276

East Asian (EAS) AF: 0.00 AC: 0 AN: 4684

South Asian (SAS) AF: 0.00 AC: 0 AN: 4424

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: 0.0000471 AC: 3 AN: 63682

Other (OTH) AF: 0.00 AC: 0 AN: 1920

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	FOXG1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rett syndrome, congenital variant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=75/25	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: rs786200975; hg19: chr14-29236703;