Genetic Variant FOXE1:p.Ala175_Ala179del (chr9-97854418-AGCCGCCGCCGCCGCC-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3BP6_Moderate

The NM_004473.4(FOXE1):c.523_537delGCCGCCGCCGCCGCC(p.Ala175_Ala179del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000348 in 1,220,048 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

FOXE1
NM_004473.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B: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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004473.4

BP6

Variant 9-97854418-AGCCGCCGCCGCCGCC-A is Benign according to our data. Variant chr9-97854418-AGCCGCCGCCGCCGCC-A is described in CliVar as Likely_benign. Clinvar id is 3910746.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-97854418-AGCCGCCGCCGCCGCC-A is described in CliVar as Likely_benign. Clinvar id is 3910746.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE1	NM_004473.4 link	c.523_537delGCCGCCGCCGCCGCC	p.Ala175_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.523_537delGCCGCCGCCGCCGCC	p.Ala175_Ala179del	conservative_inframe_deletion	Exon 1 of 1	6	NM_004473.4	ENSP00000364265.3		O00358

Frequencies

GnomAD3 genomes

AF:

0.000449

AC:

AN:

144856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000674

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000683

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00209

Gnomad SAS

AF:

0.000637

Gnomad FIN

AF:

0.000111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000498

GnomAD4 exome

AF:

0.000334

AC:

359

AN:

1075092

Hom.:

AF XY:

0.000328

AC XY:

170

AN XY:

518060

show subpopulations

African (AFR)

AF:

0.000608

AC:

AN:

21398

American (AMR)

AF:

0.000254

AC:

AN:

7872

Ashkenazi Jewish (ASJ)

AF:

0.000158

AC:

AN:

12636

East Asian (EAS)

AF:

0.00159

AC:

AN:

23844

South Asian (SAS)

AF:

0.00111

AC:

AN:

25278

European-Finnish (FIN)

AF:

0.0000397

AC:

AN:

25218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2850

European-Non Finnish (NFE)

AF:

0.000281

AC:

257

AN:

914394

Other (OTH)

AF:

0.000433

AC:

AN:

41602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

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:

0.000448

AC:

AN:

144956

Hom.:

Cov.:

AF XY:

0.000496

AC XY:

AN XY:

70600

show subpopulations

African (AFR)

AF:

0.000672

AC:

AN:

40198

American (AMR)

AF:

0.0000682

AC:

AN:

14664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3380

East Asian (EAS)

AF:

0.00209

AC:

AN:

4780

South Asian (SAS)

AF:

0.000637

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.000111

AC:

AN:

9020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

65132

Other (OTH)

AF:

0.000493

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.0

Mutation Taster

=180/20

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