14-28767441-TCACCAC-TCACCACCAC

Variant names:

• chr14-28767441-T-TCAC
• rs772407998
• NM_005249.5:c.170_172dupACC

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.170_172dupACC​(p.His57dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000408 in 1,176,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). The gene FOXG1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000078 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.23
• Publications: 0 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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005249.5
• BP6: Variant 14-28767441-T-TCAC is Benign according to our data. Variant chr14-28767441-T-TCAC is described in ClinVar as Likely_benign. ClinVar VariationId is 487209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 47 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.170_172dupACC	p.His57dup	disruptive_inframe_insertion	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.170_172dupACC	p.His57dup	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.170_172dupACC	p.His57dup	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1436_374+1438dupACC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000779 AC: 1 AN: 128424 Hom.: 0 Cov.: 31

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: 0.00

Gnomad OTH AF: 0.000573

GnomAD4 exome AF: 0.0000449 AC: 47 AN: 1047592 Hom.: 0 Cov.: 24 AF XY: 0.0000408 AC XY: 21 AN XY: 515044

African (AFR) AF: 0.00 AC: 0 AN: 21050

American (AMR) AF: 0.00 AC: 0 AN: 21868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15326

East Asian (EAS) AF: 0.00 AC: 0 AN: 17568

South Asian (SAS) AF: 0.00 AC: 0 AN: 51132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2900

European-Non Finnish (NFE) AF: 0.0000551 AC: 47 AN: 852400

Other (OTH) AF: 0.00 AC: 0 AN: 38384

GnomAD4 genome AF: 0.00000779 AC: 1 AN: 128424 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 62436

African (AFR) AF: 0.00 AC: 0 AN: 34316

American (AMR) AF: 0.00 AC: 0 AN: 13266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3104

East Asian (EAS) AF: 0.00 AC: 0 AN: 4380

South Asian (SAS) AF: 0.00 AC: 0 AN: 3872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59798

Other (OTH) AF: 0.000573 AC: 1 AN: 1744

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 disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=83/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs772407998; hg19: chr14-29236647;