1-47416738-G-C

Variant names:

• chr1-47416738-G-C
• rs145081583
• NM_012186.3:c.423G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_012186.3(FOXE3):​c.423G>C​(p.Lys141Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K141K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FOXE3 NM_012186.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.517
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a DNA_binding_region Fork-head (size 94) in uniprot entity FOXE3_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_012186.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE3	NM_012186.3	MANE Select	c.423G>C	p.Lys141Asn	missense	Exon 1 of 1	NP_036318.1
	LINC01389	NR_126355.1		n.29-6837C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE3	ENST00000335071.4	TSL:6 MANE Select	c.423G>C	p.Lys141Asn	missense	Exon 1 of 1	ENSP00000334472.2
	LINC01389	ENST00000828805.1		n.207+16625C>G		intron	N/A
	LINC01389	ENST00000828806.1		n.92+493C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458636 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725702

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110198

Other (OTH) AF: 0.00 AC: 0 AN: 60222

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		0.52
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.69		Loss of methylation at K141 (P = 0.0075)
MVP		0.92
ClinPred		1.0	D
GERP RS		3.5
PromoterAI		-0.075	Neutral
Varity_R		0.94
gMVP		0.92
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145081583; hg19: chr1-47882410;