rs1057520147

Variant names:

• chr14-28767554-C-T
• rs1057520147
• NM_005249.5:c.275C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-28767554-C-T
• chr14-28767554-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. BP4 BS2_Supporting BP5 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Ala92Val variant in FOXG1 is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). The p.Ala92Val variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - Invitae) (BP5). Computational analysis prediction tools suggest that the p.Ala92Val variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Ala92Val variant in FOXG1 is absent from gnomAD (PM2_supporting).In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 1 unaffected individual and 2 individuals with an alternate molecular diagnosis, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified this variant as Likely Benign (BS2_supporting, BP4, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16603285/MONDO:0100040/035

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: -0.593
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	NM_005249.5	MANE Select	c.275C>T	p.Ala92Val	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.275C>T	p.Ala92Val	missense	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.275C>T	p.Ala92Val	missense	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1541C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000674 AC: 1 AN: 148422 Hom.: 0 Cov.: 31

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: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000631 AC: 63 AN: 998534 Hom.: 0 Cov.: 23 AF XY: 0.0000509 AC XY: 24 AN XY: 471568

African (AFR) AF: 0.00 AC: 0 AN: 20070

American (AMR) AF: 0.00 AC: 0 AN: 6418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11064

East Asian (EAS) AF: 0.00 AC: 0 AN: 19310

South Asian (SAS) AF: 0.0000525 AC: 1 AN: 19040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2520

European-Non Finnish (NFE) AF: 0.0000717 AC: 62 AN: 864498

Other (OTH) AF: 0.00 AC: 0 AN: 37948

GnomAD4 genome AF: 0.00000674 AC: 1 AN: 148422 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 1 AN XY: 72280

African (AFR) AF: 0.00 AC: 0 AN: 40970

American (AMR) AF: 0.00 AC: 0 AN: 14918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66732

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.59
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.21	N
REVEL	Benign	0.018
Sift	Uncertain	0.015	D
Sift4G	Benign	0.27	T
Polyphen		0.0040	B
Vest4		0.024
MutPred		0.28		Gain of catalytic residue at R88 (P = 0.0196)
MVP		0.14
ClinPred		0.14	T
GERP RS		2.0
Varity_R		0.090
gMVP		0.098
Mutation Taster		=92/8	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: rs1057520147; hg19: chr14-29236760;