rs797045583

Variant names:

• chr14-28767709-G-A
• rs797045583
• NM_005249.5:c.430G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-28767709-G-A
• chr14-28767709-G-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.430G>A​(p.Glu144Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E144D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 7.21
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23763192).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.430G>A	p.Glu144Lys	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.430G>A	p.Glu144Lys	missense	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.430G>A	p.Glu144Lys	missense	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1696G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	FOXG1 disorder (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Rett syndrome, congenital variant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.0098
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		7.2
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.14	T
Polyphen		0.84	P
Vest4		0.20
MutPred		0.31		Gain of glycosylation at E144 (P = 0.0162)
MVP		0.16
ClinPred		0.88	D
GERP RS		2.9
Varity_R		0.28
gMVP		0.41
Mutation Taster		=79/21	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: rs797045583; hg19: chr14-29236915;