rs1275380745

Variant names:

• chr1-47416318-G-A
• rs1275380745
• NM_012186.3:c.3G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-47416318-G-A
• chr1-47416318-G-C
• chr1-47416318-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_012186.3(FOXE3):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000839 in 1,192,408 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: FOXE3 NM_012186.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0610
• 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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 7 codons. Genomic position: 47416334. Lost 0.020 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.3G>A	p.Met1?	start_lost	Exon 1 of 1	NP_036318.1	Q13461
	LINC01389	NR_126355.1		n.29-6417C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE3	ENST00000335071.4	TSL:6 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 1	ENSP00000334472.2	Q13461
	LINC01389	ENST00000828805.1		n.207+17045C>T		intron	N/A
	LINC01389	ENST00000828806.1		n.92+913C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.39e-7 AC: 1 AN: 1192408 Hom.: 0 Cov.: 30 AF XY: 0.00000172 AC XY: 1 AN XY: 582512

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24816

American (AMR) AF: 0.00 AC: 0 AN: 19502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18912

East Asian (EAS) AF: 0.00 AC: 0 AN: 26236

South Asian (SAS) AF: 0.00 AC: 0 AN: 51146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3328

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 974704

Other (OTH) AF: 0.00 AC: 0 AN: 47672

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Benign	-0.26
CADD	Benign	7.9
DANN	Benign	0.97
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.066	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.36	T
PhyloP100		0.061
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0030	B
Vest4		0.17
MutPred		0.96		Gain of catalytic residue at M1 (P = 0.0255)
MVP		0.67
ClinPred		0.095	T
GERP RS		1.6
PromoterAI		-0.044	Neutral
Varity_R		0.83
gMVP		0.37
Mutation Taster		=181/19	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: rs1275380745; hg19: chr1-47881990; COSMIC: COSV100624009;