1-47416235-TGGGGG-TGGGG

Variant names:

• chr1-47416235-TG-T
• rs137862650
• ENST00000828805.1:n.207+17127delC

Variant summary

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

The NR_126355.1(LINC01389):​n.29-6335delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 929,636 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (0 hom.)
• Consequence: LINC01389 NR_126355.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.312
• Publications: 0 publications found

Genes affected

LINC01389 (HGNC:50661): (long intergenic non-protein coding RNA 1389)

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]

FOXE3 Gene-Disease associations (from GenCC):

• cataract

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: G2P
• congenital primary aphakia

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• anterior segment dysgenesis 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• aortic aneurysm, familial thoracic 11, susceptibility to

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• anterior segment dysgenesis

  Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Peters anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.00837) population. However there is too low homozygotes in high coverage region: (expected more than 3, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_126355.1. 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
	LINC01389	NR_126355.1		n.29-6335delC		intron	N/A
	FOXE3	NM_012186.3	MANE Select	c.-80delG		upstream_gene	N/A	NP_036318.1	Q13461

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINC01389	ENST00000828805.1		n.207+17127delC		intron	N/A
	LINC01389	ENST00000828806.1		n.92+995delC		intron	N/A
	LINC01389	ENST00000828807.1		n.92+995delC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000919 AC: 131 AN: 142620 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000845

Gnomad SAS AF: 0.000459

Gnomad FIN AF: 0.000439

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000154

Gnomad OTH AF: 0.000510

GnomAD4 exome AF: 0.00437 AC: 3436 AN: 786946 Hom.: 0 Cov.: 12 AF XY: 0.00463 AC XY: 1740 AN XY: 376172

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

African (AFR) AF: 0.00624 AC: 95 AN: 15228

American (AMR) AF: 0.0107 AC: 50 AN: 4682

Ashkenazi Jewish (ASJ) AF: 0.00771 AC: 65 AN: 8434

East Asian (EAS) AF: 0.00587 AC: 100 AN: 17032

South Asian (SAS) AF: 0.00950 AC: 180 AN: 18948

European-Finnish (FIN) AF: 0.00901 AC: 129 AN: 14314

Middle Eastern (MID) AF: 0.00714 AC: 14 AN: 1960

European-Non Finnish (NFE) AF: 0.00392 AC: 2652 AN: 676818

Other (OTH) AF: 0.00511 AC: 151 AN: 29530

⚠️ 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 AF: 0.000918 AC: 131 AN: 142690 Hom.: 0 Cov.: 31 AF XY: 0.000878 AC XY: 61 AN XY: 69474

African (AFR) AF: 0.00262 AC: 102 AN: 38940

American (AMR) AF: 0.000555 AC: 8 AN: 14414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.000849 AC: 4 AN: 4714

South Asian (SAS) AF: 0.000460 AC: 2 AN: 4346

European-Finnish (FIN) AF: 0.000439 AC: 4 AN: 9120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000155 AC: 10 AN: 64724

Other (OTH) AF: 0.000505 AC: 1 AN: 1980

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.000971

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.31
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs137862650; hg19: chr1-47881907; COSMIC: COSV58632754;