Genetic Variant FOXE1:p.Ala177_Ala179del (chr9-97854418-AGCCGCCGCC-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_004473.4(FOXE1):c.529_537delGCCGCCGCC(p.Ala177_Ala179del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000762 in 1,201,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00073 ( 0 hom. )

Consequence

FOXE1
NM_004473.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

Publications

21 publications found

Variant links:

Genes affected

FOXE1 (HGNC:3806): (forkhead box E1) This intronless gene encodes a protein that belongs to the forkhead family of transcription factors. Members of this family contain a conserved 100-amino acid DNA-binding 'forkhead' domain. The encoded protein functions as a thyroid transcription factor that plays a role in thyroid morphogenesis. Mutations in this gene are associated with the Bamforth-Lazarus syndrome, and with susceptibility to nonmedullary thyroid cancer-4. [provided by RefSeq, Nov 2016]

FOXE1 Gene-Disease associations (from GenCC):

Bamforth-Lazarus syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, Orphanet

FOXE1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004473.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE1	NM_004473.4 link	c.529_537delGCCGCCGCC	p.Ala177_Ala179del	conservative_inframe_deletion	Exon 1 of 1	ENST00000375123.5	NP_004464.2	O00358

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXE1	ENST00000375123.5 link	c.529_537delGCCGCCGCC	p.Ala177_Ala179del	conservative_inframe_deletion	Exon 1 of 1	6	NM_004473.4	ENSP00000364265.3		O00358

Frequencies

GnomAD3 genomes

AF:

0.000946

AC:

137

AN:

144826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000546

Gnomad ASJ

AF:

0.00207

Gnomad EAS

AF:

0.00167

Gnomad SAS

AF:

0.00191

Gnomad FIN

AF:

0.000111

Gnomad MID

AF:

0.00338

Gnomad NFE

AF:

0.000629

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000737

AC:

AN:

12212

AF XY:

0.000667

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.000445

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000735

AC:

776

AN:

1056202

Hom.:

AF XY:

0.000820

AC XY:

417

AN XY:

508808

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

20874

American (AMR)

AF:

0.00195

AC:

AN:

7690

Ashkenazi Jewish (ASJ)

AF:

0.00120

AC:

AN:

12488

East Asian (EAS)

AF:

0.00169

AC:

AN:

22438

South Asian (SAS)

AF:

0.00282

AC:

AN:

24850

European-Finnish (FIN)

AF:

0.00130

AC:

AN:

24678

Middle Eastern (MID)

AF:

0.000712

AC:

AN:

2810

European-Non Finnish (NFE)

AF:

0.000579

AC:

521

AN:

899572

Other (OTH)

AF:

0.00123

AC:

AN:

40802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000959

AC:

139

AN:

144926

Hom.:

Cov.:

AF XY:

0.000737

AC XY:

AN XY:

70586

show subpopulations

African (AFR)

AF:

0.00157

AC:

AN:

40194

American (AMR)

AF:

0.000546

AC:

AN:

14658

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

3380

East Asian (EAS)

AF:

0.00167

AC:

AN:

4778

South Asian (SAS)

AF:

0.00213

AC:

AN:

4702

European-Finnish (FIN)

AF:

0.000111

AC:

AN:

9016

Middle Eastern (MID)

AF:

0.00365

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000630

AC:

AN:

65122

Other (OTH)

AF:

0.00

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 10, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of 3 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.0

Mutation Taster

=187/13

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over