rs367943249

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-47416772-G-C
• chr1-47416772-G-A

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

Sel.	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	Q13461
	LINC01389	NR_126355.1		n.29-6871C>G		intron	N/A

Ensembl Transcripts

Sel.	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	Q13461
	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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta (1)
-	1	-	Cardiovascular phenotype (1)
1	-	-	Congenital primary aphakia;C1862839:Anterior segment dysgenesis (1)
-	-	-	Aortic aneurysm, familial thoracic 11, susceptibility to (1)

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;