chr1-47416316-A-G

Variant names:

• chr1-47416316-A-G
• NM_012186.3:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_012186.3(FOXE3):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000842 in 1,187,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: FOXE3 NM_012186.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.571
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 7 codons. Genomic position: 47416334. Lost 0.020 part of the original CDS.
• 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.1A>G	p.Met1?	start_lost	Exon 1 of 1	NP_036318.1	Q13461
	LINC01389	NR_126355.1		n.29-6415T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE3	ENST00000335071.4	TSL:6 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 1	ENSP00000334472.2	Q13461
	LINC01389	ENST00000828805.1		n.207+17047T>C		intron	N/A
	LINC01389	ENST00000828806.1		n.92+915T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.42e-7 AC: 1 AN: 1187776 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 580110

African (AFR) AF: 0.00 AC: 0 AN: 24666

American (AMR) AF: 0.00 AC: 0 AN: 19234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18672

East Asian (EAS) AF: 0.00 AC: 0 AN: 26040

South Asian (SAS) AF: 0.00 AC: 0 AN: 50598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3292

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 972060

Other (OTH) AF: 0.00 AC: 0 AN: 47410

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital primary aphakia;C1862839:Anterior segment dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	1.5
DANN	Benign	0.69
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.020	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.31	T
PhyloP100		-0.57
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.96		Gain of glycosylation at S5 (P = 0.1749)
MVP		0.64
ClinPred		0.055	T
GERP RS		1.0
PromoterAI		-0.086	Neutral
Varity_R		0.85
gMVP		0.40
Mutation Taster		=181/19	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

hg19: chr1-47881988;