chr1-47416320-C-G

Variant names:

• chr1-47416320-C-G
• rs1352133719
• NM_012186.3:c.5C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012186.3(FOXE3):​c.5C>G​(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,342,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: FOXE3 NM_012186.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.245
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20816979).

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.5C>G	p.Ala2Gly	missense	Exon 1 of 1	NP_036318.1	Q13461
	LINC01389	NR_126355.1		n.29-6419G>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.5C>G	p.Ala2Gly	missense	Exon 1 of 1	ENSP00000334472.2	Q13461
	LINC01389	ENST00000828805.1		n.207+17043G>C		intron	N/A
	LINC01389	ENST00000828806.1		n.92+911G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.39e-7 AC: 1 AN: 1191712 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 582282

African (AFR) AF: 0.00 AC: 0 AN: 24820

American (AMR) AF: 0.00 AC: 0 AN: 19654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18866

East Asian (EAS) AF: 0.00 AC: 0 AN: 26160

South Asian (SAS) AF: 0.00 AC: 0 AN: 51088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3320

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 974122

Other (OTH) AF: 0.00 AC: 0 AN: 47656

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151010 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73628

African (AFR) AF: 0.00 AC: 0 AN: 41336

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

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

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67278

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.24
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.063
Sift	Benign	0.20	T
Sift4G	Benign	0.69	T
Polyphen		0.18	B
Vest4		0.098
MutPred		0.17		Loss of catalytic residue at A2 (P = 0.0923)
MVP		0.52
ClinPred		0.068	T
GERP RS		2.7
PromoterAI		-0.19	Neutral
Varity_R		0.053
gMVP		0.16
Mutation Taster		=99/1	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

dbSNP: rs1352133719; hg19: chr1-47881992;