NM_005249.5:c.10A>T

Variant names:

• chr14-28767289-A-T
• rs1466463571
• NM_005249.5:c.10A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005249.5(FOXG1):​c.10A>T​(p.Met4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,384,910 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M4V) has been classified as Uncertain significance. The gene FOXG1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 30)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22957993).

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.10A>T	p.Met4Leu	missense	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.10A>T	p.Met4Leu	missense	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.10A>T	p.Met4Leu	missense	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1276A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000707 AC: 1 AN: 141406 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.04e-7 AC: 1 AN: 1243504 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 616816

African (AFR) AF: 0.00 AC: 0 AN: 25142

American (AMR) AF: 0.00 AC: 0 AN: 32444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18032

East Asian (EAS) AF: 0.00 AC: 0 AN: 22510

South Asian (SAS) AF: 0.00 AC: 0 AN: 76554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4702

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 977694

Other (OTH) AF: 0.00 AC: 0 AN: 46168

GnomAD4 genome AF: 0.00000707 AC: 1 AN: 141406 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 68594

African (AFR) AF: 0.00 AC: 0 AN: 38812

American (AMR) AF: 0.00 AC: 0 AN: 14180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3326

East Asian (EAS) AF: 0.00 AC: 0 AN: 4768

South Asian (SAS) AF: 0.00 AC: 0 AN: 4546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 64832

Other (OTH) AF: 0.00 AC: 0 AN: 1956

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.81	L
PhyloP100		1.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0030	B
Vest4		0.27
MutPred		0.31		Loss of MoRF binding (P = 0.0735)
MVP		0.46
ClinPred		0.48	T
GERP RS		2.0
Varity_R		0.87
gMVP		0.58
Mutation Taster		=85/15	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: rs1466463571; hg19: chr14-29236495;