rs1057518738

Positions:

• chr1-47416622-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_012186.3(FOXE3):​c.307G>A​(p.Glu103Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E103E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXE3 NM_012186.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.94

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_012186.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-47416622-G-A is Pathogenic according to our data. Variant chr1-47416622-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 372170.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-47416622-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXE3	NM_012186.3	c.307G>A	p.Glu103Lys	missense_variant	1/1	ENST00000335071.4	NP_036318.1
LINC01389	NR_126355.1	n.29-6721C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXE3	ENST00000335071.4	c.307G>A	p.Glu103Lys	missense_variant	1/1	6	NM_012186.3	ENSP00000334472.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 34 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	0.70	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.055	T
Polyphen		0.99	D
Vest4		0.30
MutPred		0.46		Gain of MoRF binding (P = 0.0034);
MVP		0.83
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.54
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518738; hg19: chr1-47882294;