rs866815665

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-28767530-C-A
• chr14-28767530-C-G
• chr14-28767530-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BP5_Strong BS2

This summary comes from the ClinGen Evidence Repository: The p.Pro84His variant in FOXG1 is present in 1 individual in gnomAD (0.0039%) (not sufficient to meet BS1 criteria). The p.Pro84His variant is observed in at least 20 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro84His variant is found in at least 4 patients with an alternate molecular basis of disease (internal database - Invitae; internal database - GeneDx) (BP5_strong). Computational analysis prediction tools suggest that the p.Pro84His variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro84His variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS2, BP5_strong, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16606972/MONDO:0100040/035

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:4
• Conservation: PhyloP100: 0.467
• 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: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

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.251C>A	p.Pro84His	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.251C>A	p.Pro84His	missense	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.251C>A	p.Pro84His	missense	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1517C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000204 AC: 3 AN: 147192 Hom.: 0 Cov.: 32

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: 0.0000453

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000152 AC: 14 AN: 919386 Hom.: 0 Cov.: 17 AF XY: 0.0000162 AC XY: 7 AN XY: 432900

African (AFR) AF: 0.00 AC: 0 AN: 17924

American (AMR) AF: 0.000246 AC: 1 AN: 4062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8376

East Asian (EAS) AF: 0.00 AC: 0 AN: 11994

South Asian (SAS) AF: 0.00 AC: 0 AN: 17946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11736

Middle Eastern (MID) AF: 0.000470 AC: 1 AN: 2128

European-Non Finnish (NFE) AF: 0.0000135 AC: 11 AN: 812058

Other (OTH) AF: 0.0000302 AC: 1 AN: 33162

GnomAD4 genome AF: 0.0000204 AC: 3 AN: 147192 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71600

African (AFR) AF: 0.00 AC: 0 AN: 40826

American (AMR) AF: 0.00 AC: 0 AN: 14804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000453 AC: 3 AN: 66222

Other (OTH) AF: 0.00 AC: 0 AN: 2026

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	FOXG1 disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Rett syndrome, congenital variant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.47
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.32	N
REVEL	Benign	0.015
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.12	T
Polyphen		0.15	B
Vest4		0.12
MutPred		0.28		Gain of catalytic residue at P79 (P = 0.0047)
MVP		0.21
ClinPred		0.26	T
GERP RS		2.0
Varity_R		0.18
gMVP		0.16
Mutation Taster		=90/10	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: rs866815665; hg19: chr14-29236736;