14-28767417-GCACCACCACCACCAC-GCAC

Variant names:

• chr14-28767417-GCACCACCACCAC-G
• rs587783630
• NM_005249.5:c.150_161delCCACCACCACCA

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.150_161delCCACCACCACCA​(p.His51_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 0.00000577 in 1,385,704 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), 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. H50H) has been classified as Likely benign. The gene FOXG1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.54
• 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 5 benign, 8 uncertain in NM_005249.5
• BP3: Nonframeshift variant in repetitive region in NM_005249.5
• BP6: Variant 14-28767417-GCACCACCACCAC-G is Benign according to our data. Variant chr14-28767417-GCACCACCACCAC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1773994.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.150_161delCCACCACCACCA	p.His51_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.150_161delCCACCACCACCA	p.His51_His54del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.150_161delCCACCACCACCA	p.His51_His54del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1416_374+1427delCCACCACCACCA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000140 AC: 2 AN: 143124 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000307

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 6 AN: 1242504 Hom.: 0 AF XY: 0.00000488 AC XY: 3 AN XY: 615214

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

African (AFR) AF: 0.00 AC: 0 AN: 25398

American (AMR) AF: 0.00 AC: 0 AN: 30694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19030

East Asian (EAS) AF: 0.0000405 AC: 1 AN: 24694

South Asian (SAS) AF: 0.00 AC: 0 AN: 72988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4008

European-Non Finnish (NFE) AF: 0.00000511 AC: 5 AN: 978036

Other (OTH) AF: 0.00 AC: 0 AN: 46876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00884398), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000140 AC: 2 AN: 143200 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 69514

African (AFR) AF: 0.00 AC: 0 AN: 39450

American (AMR) AF: 0.00 AC: 0 AN: 14528

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4878

South Asian (SAS) AF: 0.00 AC: 0 AN: 4532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.0000308 AC: 2 AN: 65040

Other (OTH) AF: 0.00 AC: 0 AN: 1958

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	FOXG1 disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=172/28	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs587783630; hg19: chr14-29236623;