rs587783629

Variant names:

• chr14-28767410-AC-A
• rs587783629
• NM_005249.5:c.136delC

Your query was ambiguous. Multiple possible variants found:

• chr14-28767410-AC-A
• chr14-28767410-AC-ACC
• chr14-28767410-AC-ACCC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_005249.5(FOXG1):​c.136delC​(p.Gln46SerfsTer146) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000709 in 1,269,734 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q46Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: FOXG1 NM_005249.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.127
• Publications: 2 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_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 271 pathogenic variants in the truncated region.

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.136delC	p.Gln46SerfsTer146	frameshift	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.136delC	p.Gln46SerfsTer146	frameshift	Exon 1 of 1	ENSP00000339004.3
	FOXG1	ENST00000706482.1		c.136delC	p.Gln46SerfsTer146	frameshift	Exon 2 of 2	ENSP00000516406.1
	LINC01551	ENST00000675861.1		n.374+1402delC		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000653 AC: 1 AN: 153056 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000423

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000709 AC: 9 AN: 1269734 Hom.: 0 Cov.: 31 AF XY: 0.00000159 AC XY: 1 AN XY: 629702

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26114

American (AMR) AF: 0.0000624 AC: 2 AN: 32040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19724

East Asian (EAS) AF: 0.0000381 AC: 1 AN: 26222

South Asian (SAS) AF: 0.00 AC: 0 AN: 74810

European-Finnish (FIN) AF: 0.0000233 AC: 1 AN: 42970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4094

European-Non Finnish (NFE) AF: 0.00000502 AC: 5 AN: 995432

Other (OTH) AF: 0.00 AC: 0 AN: 48328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.13

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: rs587783629; hg19: chr14-29236616;