NM_005249.5:c.218_220delAGC

Variant names:

• chr14-28767485-CGCA-C
• rs398124201
• NM_005249.5:c.218_220delAGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_005249.5(FOXG1):​c.218_220delAGC​(p.Gln73del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,054,954 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 (★). Synonymous variant affecting the same amino acid position (i.e. Q73Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.869
• 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 -2 ACMG points.

• BP6: Variant 14-28767485-CGCA-C is Benign according to our data. Variant chr14-28767485-CGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 1123192.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.218_220delAGC	p.Gln73del	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.218_220delAGC	p.Gln73del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.218_220delAGC	p.Gln73del	disruptive_inframe_deletion	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1484_374+1486delAGC		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000278 AC: 4 AN: 143906 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: 0.000202

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000460

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000476 AC: 3 AN: 62992 AF XY: 0.0000274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000445

Gnomad NFE exome AF: 0.0000431

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000538 AC: 49 AN: 910960 Hom.: 0 AF XY: 0.0000477 AC XY: 21 AN XY: 440222

⚠️ 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: 18248

American (AMR) AF: 0.0000598 AC: 1 AN: 16728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11830

East Asian (EAS) AF: 0.00 AC: 0 AN: 11304

South Asian (SAS) AF: 0.0000300 AC: 1 AN: 33366

European-Finnish (FIN) AF: 0.000219 AC: 3 AN: 13704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2172

European-Non Finnish (NFE) AF: 0.0000544 AC: 42 AN: 771376

Other (OTH) AF: 0.0000621 AC: 2 AN: 32232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000278 AC: 4 AN: 143994 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 1 AN XY: 70064

African (AFR) AF: 0.00 AC: 0 AN: 39870

American (AMR) AF: 0.00 AC: 0 AN: 14578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3322

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4932

South Asian (SAS) AF: 0.00 AC: 0 AN: 4662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000460 AC: 3 AN: 65178

Other (OTH) AF: 0.00 AC: 0 AN: 1984

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome, congenital variant Benign:1

Jun 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.87
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: rs398124201; hg19: chr14-29236691;