14-28767417-GCACCACCACCACCAC-GCACCACCACCAC

Variant names:

• chr14-28767417-GCAC-G
• rs587783630
• NM_005249.5:c.159_161delCCA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP3 BP6_Very_Strong

The NM_005249.5(FOXG1):​c.159_161delCCA​(p.His54del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,371,964 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H53H) has been classified as Likely benign. The gene FOXG1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.54
• 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

Specifications for FOXG1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in NM_005249.5
• BP3: Nonframeshift variant in repetitive region in NM_005249.5
• BP6: Variant 14-28767417-GCAC-G is Benign according to our data. Variant chr14-28767417-GCAC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.159_161delCCA	p.His54del	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.159_161delCCA	p.His54del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.159_161delCCA	p.His54del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1425_374+1427delCCA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000419 AC: 6 AN: 143112 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000689

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000615

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00149 AC: 209 AN: 139964 AF XY: 0.00142

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.000655

Gnomad EAS exome AF: 0.000814

Gnomad FIN exome AF: 0.00228

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00191 AC: 2344 AN: 1228852 Hom.: 0 AF XY: 0.00196 AC XY: 1190 AN XY: 607594

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

African (AFR) AF: 0.00199 AC: 50 AN: 25148

American (AMR) AF: 0.00194 AC: 59 AN: 30382

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 54 AN: 18734

East Asian (EAS) AF: 0.00442 AC: 107 AN: 24186

South Asian (SAS) AF: 0.00287 AC: 205 AN: 71346

European-Finnish (FIN) AF: 0.00385 AC: 154 AN: 40040

Middle Eastern (MID) AF: 0.00228 AC: 9 AN: 3954

European-Non Finnish (NFE) AF: 0.00166 AC: 1610 AN: 968740

Other (OTH) AF: 0.00207 AC: 96 AN: 46322

⚠️ 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: 0.0000419 AC: 6 AN: 143112 Hom.: 0 Cov.: 30 AF XY: 0.0000432 AC XY: 3 AN XY: 69418

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

African (AFR) AF: 0.00 AC: 0 AN: 39354

American (AMR) AF: 0.0000689 AC: 1 AN: 14506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3340

East Asian (EAS) AF: 0.00 AC: 0 AN: 4890

South Asian (SAS) AF: 0.00 AC: 0 AN: 4542

European-Finnish (FIN) AF: 0.000120 AC: 1 AN: 8318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0000615 AC: 4 AN: 65048

Other (OTH) AF: 0.00 AC: 0 AN: 1936

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0316511), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00175 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	FOXG1 disorder (1)
-	-	1	FOXG1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
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: rs587783630; hg19: chr14-29236623; COSMIC: COSV57398055; COSMIC: COSV57398055;