14-28767530-C-T

Variant names:

• chr14-28767530-C-T
• rs866815665
• NM_005249.5:c.251C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2 PP2 BP4_Moderate BP6_Moderate BS2

The NM_005249.5(FOXG1):​c.251C>T​(p.Pro84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000544 in 919,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P84H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.467

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 Likely_benign. Variant got -5 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08874446).
• BP6: Variant 14-28767530-C-T is Benign according to our data. Variant chr14-28767530-C-T is described in ClinVar as [Benign]. Clinvar id is 1059283.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.251C>T	p.Pro84Leu	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.251C>T	p.Pro84Leu	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.251C>T	p.Pro84Leu	missense_variant	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1517C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000544 AC: 5 AN: 919384 Hom.: 0 Cov.: 17 AF XY: 0.00000462 AC XY: 2 AN XY: 432902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000616

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome, congenital variant Benign:1

Mar 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.027
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.24	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.29		Gain of catalytic residue at P79 (P = 0.0047);
MVP		0.21
ClinPred		0.25	T
GERP RS		2.0
Varity_R		0.099
gMVP		0.16

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: rs866815665; hg19: chr14-29236736;