14-28767441-TCACCAC-TCAC

Variant names:

• chr14-28767441-TCAC-T
• rs772407998
• NM_005249.5:c.170_172delACC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005249.5(FOXG1):​c.170_172delACC​(p.His57del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,047,576 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.170_172delACC	p.His57del	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.170_172delACC	p.His57del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.170_172delACC	p.His57del	disruptive_inframe_deletion	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1436_374+1438delACC		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000286 AC: 3 AN: 1047576 Hom.: 0 AF XY: 0.00000388 AC XY: 2 AN XY: 515032

⚠️ 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: 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: 51130

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: 0.00000352 AC: 3 AN: 852386

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

⚠️ 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 Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

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: rs772407998; hg19: chr14-29236647;