14-28767262-C-G

Variant names:

• chr14-28767262-C-G
• rs1057523422
• NM_005249.5:c.-18C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005249.5(FOXG1):​c.-18C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000856 in 1,168,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: FOXG1 NM_005249.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.326
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

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.-18C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	NP_005240.3
	FOXG1	NM_005249.5	MANE Select	c.-18C>G		5_prime_UTR	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.-18C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.-18C>G		5_prime_UTR	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.-18C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000516406.1	P55316

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.56e-7 AC: 1 AN: 1168138 Hom.: 0 Cov.: 32 AF XY: 0.00000173 AC XY: 1 AN XY: 576722

⚠️ 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: 22596

American (AMR) AF: 0.00 AC: 0 AN: 25502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15918

East Asian (EAS) AF: 0.00 AC: 0 AN: 16864

South Asian (SAS) AF: 0.00 AC: 0 AN: 68954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4408

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 934584

Other (OTH) AF: 0.00 AC: 0 AN: 42246

⚠️ 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 Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		-0.33
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1057523422; hg19: chr14-29236468;