NM_005249.5:c.1256C>T

Variant names:

• chr14-28768535-C-T
• rs1555321437
• NM_005249.5:c.1256C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_005249.5(FOXG1):​c.1256C>T​(p.Pro419Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.75

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the FOXG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 90 curated pathogenic missense variants (we use a threshold of 10). The gene has 66 curated benign missense variants. Trascript score misZ: 3.7891 (above the threshold of 3.09). GenCC associations: The gene is linked to Rett syndrome, congenital variant, FOXG1 disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.1256C>T	p.Pro419Leu	missense_variant	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.1256C>T	p.Pro419Leu	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.1256C>T	p.Pro419Leu	missense_variant	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+2522C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental abnormality Uncertain:1

-

Institute of Human Genetics, University of Wuerzburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Oct 26, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome, congenital variant Uncertain:1

May 19, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_MOD, PM2_SUP, PP2_SUP, PP3_SUP -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.41		Gain of catalytic residue at P419 (P = 0.0107);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.69
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555321437; hg19: chr14-29237741;