rs928328635

Variant names:

• chr1-47416321-G-A
• rs928328635
• NM_012186.3:c.6G>A
• FOXE3 p.Ala2Ala

Your query was ambiguous. Multiple possible variants found:

• chr1-47416321-G-A
• chr1-47416321-G-C
• chr1-47416321-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_012186.3(FOXE3):​c.6G>A​(p.Ala2Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 151,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXE3 NM_012186.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.27
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-47416321-G-A is Benign according to our data. Variant chr1-47416321-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2448365.
• BP7: Synonymous conserved (PhyloP=-3.27 with no splicing effect.

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.6G>A	p.Ala2Ala	synonymous	Exon 1 of 1	NP_036318.1	Q13461
	LINC01389	NR_126355.1		n.29-6420C>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.6G>A	p.Ala2Ala	synonymous	Exon 1 of 1	ENSP00000334472.2	Q13461
	LINC01389	ENST00000828805.1		n.207+17042C>T		intron	N/A
	LINC01389	ENST00000828806.1		n.92+910C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 151106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1196362 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 584870

African (AFR) AF: 0.00 AC: 0 AN: 24900

American (AMR) AF: 0.00 AC: 0 AN: 19846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19198

East Asian (EAS) AF: 0.00 AC: 0 AN: 26262

South Asian (SAS) AF: 0.00 AC: 0 AN: 51926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3342

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 976820

Other (OTH) AF: 0.00 AC: 0 AN: 47854

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 151106 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73674

African (AFR) AF: 0.000121 AC: 5 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67342

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Congenital primary aphakia;C1862839:Anterior segment dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.80
DANN	Benign	0.89
PhyloP100		-3.3
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs928328635; hg19: chr1-47881993;