chr1-47416328-A-AG

Variant names:

• chr1-47416328-A-AG
• NM_012186.3:c.14dupG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_012186.3(FOXE3):​c.14dupG​(p.Ser5ArgfsTer280) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,210,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: FOXE3 NM_012186.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.294
• Publications: 0 publications found

Genes affected

FOXE3 (HGNC:3808): (forkhead box E3) This intronless gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. The protein encoded functions as a lens-specific transcription factor and plays an important role in vertebrate lens formation. Mutations in this gene are associated with anterior segment mesenchymal dysgenesis and congenital primary aphakia. [provided by RefSeq, Dec 2009]

LINC01389 (HGNC:50661): (long intergenic non-protein coding RNA 1389)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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 38 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012186.3. 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
	FOXE3	NM_012186.3	MANE Select	c.14dupG	p.Ser5ArgfsTer280	frameshift	Exon 1 of 1	NP_036318.1	Q13461
	LINC01389	NR_126355.1		n.29-6428dupC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE3	ENST00000335071.4	TSL:6 MANE Select	c.14dupG	p.Ser5ArgfsTer280	frameshift	Exon 1 of 1	ENSP00000334472.2	Q13461
	LINC01389	ENST00000828805.1		n.207+17034dupC		intron	N/A
	LINC01389	ENST00000828806.1		n.92+902dupC		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000165 AC: 2 AN: 1210768 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 593318

African (AFR) AF: 0.00 AC: 0 AN: 25224

American (AMR) AF: 0.00 AC: 0 AN: 21592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19864

East Asian (EAS) AF: 0.00 AC: 0 AN: 26380

South Asian (SAS) AF: 0.00 AC: 0 AN: 55292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3398

European-Non Finnish (NFE) AF: 0.00000203 AC: 2 AN: 983856

Other (OTH) AF: 0.00 AC: 0 AN: 48404

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29

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

hg19: chr1-47882000;