rs181190356

Variant names:

• chr1-47416302-G-A
• rs181190356
• NM_012186.3:c.-14G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-47416302-G-A
• chr1-47416302-G-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE3	NM_012186.3	MANE Select	c.-14G>A		5_prime_UTR	Exon 1 of 1	NP_036318.1
	LINC01389	NR_126355.1		n.29-6401C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE3	ENST00000335071.4	TSL:6 MANE Select	c.-14G>A		5_prime_UTR	Exon 1 of 1	ENSP00000334472.2
	LINC01389	ENST00000828805.1		n.207+17061C>T		intron	N/A
	LINC01389	ENST00000828806.1		n.92+929C>T		intron	N/A

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

GnomAD2 exomes AF: 0.0812 AC: 2894 AN: 35650 AF XY: 0.0845

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 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

African (AFR) AF: 0.0227 AC: 550 AN: 24274

American (AMR) AF: 0.109 AC: 1855 AN: 16974

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 455 AN: 17236

East Asian (EAS) AF: 0.156 AC: 4064 AN: 26040

South Asian (SAS) AF: 0.128 AC: 5890 AN: 45924

European-Finnish (FIN) AF: 0.0489 AC: 1224 AN: 25046

Middle Eastern (MID) AF: 0.0671 AC: 217 AN: 3232

European-Non Finnish (NFE) AF: 0.0255 AC: 24530 AN: 963552

Other (OTH) AF: 0.0497 AC: 2325 AN: 46758

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

African (AFR) AF: 0.0244 AC: 1013 AN: 41436

American (AMR) AF: 0.0833 AC: 1269 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 91 AN: 3418

East Asian (EAS) AF: 0.188 AC: 958 AN: 5094

South Asian (SAS) AF: 0.135 AC: 652 AN: 4816

European-Finnish (FIN) AF: 0.0562 AC: 592 AN: 10528

Middle Eastern (MID) AF: 0.0517 AC: 15 AN: 290

European-Non Finnish (NFE) AF: 0.0272 AC: 1830 AN: 67228

Other (OTH) AF: 0.0429 AC: 90 AN: 2096

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 31, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 11, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Jun 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29461140)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		0.36
PromoterAI		0.25	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs181190356; hg19: chr1-47881974;