1-47416302-G-A

Position:

• chr1-47416302-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012186.3(FOXE3):​c.-14G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,320,086 control chromosomes in the GnomAD database, including 1,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (250 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1411 hom.)
• Consequence: FOXE3 NM_012186.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.356

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-47416302-G-A is Benign according to our data. Variant chr1-47416302-G-A is described in ClinVar as [Benign]. Clinvar id is 260210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXE3	NM_012186.3	c.-14G>A		5_prime_UTR_variant	1/1	ENST00000335071.4
LINC01389	NR_126355.1	n.29-6401C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXE3	ENST00000335071.4	c.-14G>A		5_prime_UTR_variant	1/1		NM_012186.3	P1

Frequencies

GnomAD3 genomes AF: 0.0431 AC: 6499 AN: 150946 Hom.: 249 Cov.: 32

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0829

Gnomad ASJ AF: 0.0266

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.0545

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0376

GnomAD3 exomes AF: 0.0812 AC: 2894 AN: 35650 Hom.: 189 AF XY: 0.0845 AC XY: 1731 AN XY: 20484

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0297

Gnomad EAS exome AF: 0.248

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0600

GnomAD4 exome AF: 0.0352 AC: 41110 AN: 1169036 Hom.: 1411 Cov.: 30 AF XY: 0.0367 AC XY: 20859 AN XY: 568874

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0489

Gnomad4 NFE exome AF: 0.0255

Gnomad4 OTH exome AF: 0.0497

GnomAD4 genome AF: 0.0431 AC: 6516 AN: 151050 Hom.: 250 Cov.: 32 AF XY: 0.0484 AC XY: 3571 AN XY: 73712

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.0833

Gnomad4 ASJ AF: 0.0266

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.135

Gnomad4 FIN AF: 0.0562

Gnomad4 NFE AF: 0.0272

Gnomad4 OTH AF: 0.0429

Alfa AF: 0.00567 Hom.: 1

Bravo AF: 0.0425

Asia WGS AF: 0.185 AC: 631 AN: 3418

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2023	Variant summary: FOXE3 c.-14G>A alters a non-conserved nucleotide located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.081 in 35650 control chromosomes in the gnomAD database, including 189 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in FOXE3 causing Aortic Aneurysm, Familial Thoracic 11 phenotype (6.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.-14G>A in individuals affected with Aortic Aneurysm, Familial Thoracic 11 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	This variant is associated with the following publications: (PMID: 29461140) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Uncertain	0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs181190356; hg19: chr1-47881974;