1-47416772-G-C

Variant names:

• chr1-47416772-G-C
• rs367943249
• NM_012186.3:c.457G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_012186.3(FOXE3):​c.457G>C​(p.Asp153His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,599,660 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FOXE3 NM_012186.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 1.79
• Publications: 9 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 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant 1-47416772-G-C is Pathogenic according to our data. Variant chr1-47416772-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375651.

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.457G>C	p.Asp153His	missense	Exon 1 of 1	NP_036318.1
	LINC01389	NR_126355.1		n.29-6871C>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.457G>C	p.Asp153His	missense	Exon 1 of 1	ENSP00000334472.2
	LINC01389	ENST00000828805.1		n.207+16591C>G		intron	N/A
	LINC01389	ENST00000828806.1		n.92+459C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 8 AN: 150692 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000621 AC: 9 AN: 1448968 Hom.: 0 Cov.: 33 AF XY: 0.00000555 AC XY: 4 AN XY: 720916

African (AFR) AF: 0.00 AC: 0 AN: 32168

American (AMR) AF: 0.00 AC: 0 AN: 43324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 38316

South Asian (SAS) AF: 0.00 AC: 0 AN: 84780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 0.00000814 AC: 9 AN: 1106134

Other (OTH) AF: 0.00 AC: 0 AN: 59786

GnomAD4 genome AF: 0.0000531 AC: 8 AN: 150692 Hom.: 0 Cov.: 32 AF XY: 0.0000408 AC XY: 3 AN XY: 73582

African (AFR) AF: 0.0000242 AC: 1 AN: 41312

American (AMR) AF: 0.00 AC: 0 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67626

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital primary aphakia;C1862839:Anterior segment dysgenesis Pathogenic:1

Dec 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 153 of the FOXE3 protein (p.Asp153His). This variant is present in population databases (rs367943249, gnomAD 0.007%). This missense change has been observed in individual(s) with thoracic aortic dissections (PMID: 26854927). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 375651). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FOXE3 protein function. For these reasons, this variant has been classified as Pathogenic.

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta Pathogenic:1

Feb 08, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Cardiovascular phenotype Uncertain:1

Aug 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D153H variant (also known as c.457G>C), located in coding exon 1 of the FOXE3 gene, results from a G to C substitution at nucleotide position 457. The aspartic acid at codon 153 is replaced by histidine, an amino acid with similar properties. This alteration has been shown to segregate with disease in a family with thoracic aortic aneurysm and dissection (TAAD) (Kuang SQ et al. J Clin Invest, 2016 Mar;126:948-61). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Aortic aneurysm, familial thoracic 11, susceptibility to Other:1

Jan 06, 2018

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.86
ClinPred		1.0	D
GERP RS		3.5
PromoterAI		-0.23	Neutral
Varity_R		0.85
gMVP		0.76
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs367943249; hg19: chr1-47882444;