14-28767417-GCACCACCACCACCAC-GCACCACCACCACCACCACCAC

Variant names:

• chr14-28767417-G-GCACCAC
• rs587783630
• NM_005249.5:c.156_161dupCCACCA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_Moderate

The NM_005249.5(FOXG1):​c.156_161dupCCACCA​(p.His53_His54dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000433 in 1,385,644 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. H54H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.512
• 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: Likely_benign. The variant received -3 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005249.5
• BP6: Variant 14-28767417-G-GCACCAC is Benign according to our data. Variant chr14-28767417-G-GCACCAC is described in ClinVar as Likely_benign. ClinVar VariationId is 1085933.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.156_161dupCCACCA	p.His53_His54dup	disruptive_inframe_insertion	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_161dupCCACCA	p.His53_His54dup	disruptive_inframe_insertion	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.156_161dupCCACCA	p.His53_His54dup	disruptive_inframe_insertion	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1422_374+1427dupCCACCA		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000140 AC: 2 AN: 143126 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: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000143 AC: 2 AN: 139964 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: 0.000271

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000322 AC: 4 AN: 1242518 Hom.: 0 Cov.: 30 AF XY: 0.00000325 AC XY: 2 AN XY: 615220

African (AFR) AF: 0.0000394 AC: 1 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: 0.00 AC: 0 AN: 24694

South Asian (SAS) AF: 0.00 AC: 0 AN: 72994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40782

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

European-Non Finnish (NFE) AF: 0.00000204 AC: 2 AN: 978040

Other (OTH) AF: 0.0000213 AC: 1 AN: 46878

GnomAD4 genome AF: 0.0000140 AC: 2 AN: 143126 Hom.: 0 Cov.: 30 AF XY: 0.0000288 AC XY: 2 AN XY: 69430

African (AFR) AF: 0.00 AC: 0 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: 0.000220 AC: 1 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: 0.0000154 AC: 1 AN: 65052

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

Alfa AF: 0.00 Hom.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome, congenital variant Benign:1

Mar 21, 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		0.51
Mutation Taster		=79/21	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;