14-28767417-GCAC-G

Position:

• chr14-28767417-GCAC-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005249.5(FOXG1):​c.159_161delCCA​(p.His54del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,371,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: FOXG1 NM_005249.5 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.54

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 14-28767417-GCAC-G is Benign according to our data. Variant chr14-28767417-GCAC-G is described in ClinVar as [Likely_benign]. Clinvar id is 158588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-28767417-GCAC-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00191 (2344/1228852) while in subpopulation EAS AF= 0.00442 (107/24186). AF 95% confidence interval is 0.00374. There are 0 homozygotes in gnomad4_exome. There are 1190 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.159_161delCCA	p.His54del	disruptive_inframe_deletion	1/1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.159_161delCCA	p.His54del	disruptive_inframe_deletion	1/1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.159_161delCCA	p.His54del	disruptive_inframe_deletion	2/2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1425_374+1427delCCA		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000419 AC: 6 AN: 143112 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000689

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000615

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00191 AC: 2344 AN: 1228852 Hom.: 0 AF XY: 0.00196 AC XY: 1190 AN XY: 607594

Gnomad4 AFR exome AF: 0.00199

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.00288

Gnomad4 EAS exome AF: 0.00442

Gnomad4 SAS exome AF: 0.00287

Gnomad4 FIN exome AF: 0.00385

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.0000419 AC: 6 AN: 143112 Hom.: 0 Cov.: 30 AF XY: 0.0000432 AC XY: 3 AN XY: 69418

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000689

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000120

Gnomad4 NFE AF: 0.0000615

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2019

This alteration is classified as 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. -

FOXG1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Rett syndrome, congenital variant Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs587783630; hg19: chr14-29236623;