14-28767417-GCACCACCACCACCAC-GCACCACCAC

Variant names:

• chr14-28767417-GCACCAC-G
• rs587783630
• NM_005249.5:c.156_161delCCACCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_005249.5(FOXG1):​c.156_161delCCACCA​(p.His53_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 0.0000426 in 1,385,244 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.89
• 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.

• BP3: Nonframeshift variant in repetitive region in NM_005249.5
• BP6: Variant 14-28767417-GCACCAC-G is Benign according to our data. Variant chr14-28767417-GCACCAC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 569855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.156_161delCCACCA	p.His53_His54del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.156_161delCCACCA	p.His53_His54del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.156_161delCCACCA	p.His53_His54del	disruptive_inframe_deletion	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1422_374+1427delCCACCA		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000210 AC: 3 AN: 143126 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000762

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000500 AC: 7 AN: 139964 AF XY: 0.0000392

Gnomad AFR exome AF: 0.000162

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000136

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 56 AN: 1242118 Hom.: 0 AF XY: 0.0000504 AC XY: 31 AN XY: 615016

⚠️ 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: 25382

American (AMR) AF: 0.000228 AC: 7 AN: 30678

Ashkenazi Jewish (ASJ) AF: 0.000105 AC: 2 AN: 19020

East Asian (EAS) AF: 0.000122 AC: 3 AN: 24670

South Asian (SAS) AF: 0.0000822 AC: 6 AN: 72952

European-Finnish (FIN) AF: 0.0000491 AC: 2 AN: 40746

Middle Eastern (MID) AF: 0.000250 AC: 1 AN: 4004

European-Non Finnish (NFE) AF: 0.0000327 AC: 32 AN: 977798

Other (OTH) AF: 0.0000640 AC: 3 AN: 46868

⚠️ 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: 0.0000210 AC: 3 AN: 143126 Hom.: 0 Cov.: 30 AF XY: 0.0000288 AC XY: 2 AN XY: 69430

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

African (AFR) AF: 0.0000762 AC: 3 AN: 39358

American (AMR) AF: 0.00 AC: 0 AN: 14508

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: 0.00 AC: 0 AN: 8322

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65052

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 = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 26, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FOXG1: BP3 -

Rett syndrome, congenital variant Benign:1

Jan 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=176/24	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;