rs587783633

chr14-28767488-A-Cchr14-28767488-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_005249.5(FOXG1):c.209A>C(p.Gln70Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,011,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.693

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 -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FOXG1
• BP4: Computational evidence support a benign effect (MetaRNN=0.07108414).
• BP6: Variant 14-28767488-A-C is Benign according to our data. Variant chr14-28767488-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158591.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5	c.209A>C	p.Gln70Pro	missense_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXG1	ENST00000313071.7	c.209A>C	p.Gln70Pro	missense_variant	1/1		NM_005249.5	P1
FOXG1	ENST00000706482.1	c.209A>C	p.Gln70Pro	missense_variant	2/2			P1
LINC01551	ENST00000675861.1	n.374+1475A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000272 AC: 38 AN: 139852 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000773

Gnomad ASJ AF: 0.000307

Gnomad EAS AF: 0.000846

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00370

Gnomad NFE AF: 0.000219

Gnomad OTH AF: 0.00157

GnomAD3 exomes AF: 0.000138 AC: 5 AN: 36220 Hom.: 0 AF XY: 0.000178 AC XY: 4 AN XY: 22444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 132 AN: 871366 Hom.: 0 Cov.: 16 AF XY: 0.000141 AC XY: 59 AN XY: 418988

Gnomad4 AFR exome AF: 0.000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000950

Gnomad4 SAS exome AF: 0.000195

Gnomad4 FIN exome AF: 0.0000827

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.000164

GnomAD4 genome AF: 0.000264 AC: 37 AN: 139948 Hom.: 0 Cov.: 31 AF XY: 0.000206 AC XY: 14 AN XY: 68106

Gnomad4 AFR AF: 0.0000779

Gnomad4 AMR AF: 0.000772

Gnomad4 ASJ AF: 0.000307

Gnomad4 EAS AF: 0.000849

Gnomad4 SAS AF: 0.000224

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000219

Gnomad4 OTH AF: 0.00155

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000366

ExAC AF: 0.0000714 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rett syndrome, congenital variant Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 17, 2021	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	16
Dann	Benign	0.78
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.035
Sift	Benign	0.35	T
Sift4G	Benign	0.29	T
Polyphen		0.80	P
Vest4		0.33
MutPred		0.32		Gain of catalytic residue at P65 (P = 5e-04);
MVP		0.040
ClinPred		0.041	T
GERP RS		0.93
Varity_R		0.089
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: rs587783633; hg19: chr14-29236694;