Genetic Variant FOXE1:p.Ala179del (chr9-97854418-AGCC-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.535_537delGCC(p.Ala179del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,218,460 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 0.00019 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

FOXE1
NM_004473.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.56

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: Laboratory for Molecular Medicine, G2P, Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

FOXE1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004473.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004473.4. 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
	FOXE1	NM_004473.4	MANE Select	c.535_537delGCC	p.Ala179del	conservative_inframe_deletion	Exon 1 of 1	NP_004464.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE1	ENST00000375123.5	TSL:6 MANE Select	c.535_537delGCC	p.Ala179del	conservative_inframe_deletion	Exon 1 of 1	ENSP00000364265.3	O00358

Frequencies

GnomAD3 genomes

AF:

0.000193

AC:

AN:

144846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000273

Gnomad ASJ

AF:

0.000888

Gnomad EAS

AF:

0.000834

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000123

Gnomad OTH

AF:

0.000498

GnomAD4 exome

AF:

0.000379

AC:

407

AN:

1073514

Hom.:

AF XY:

0.000433

AC XY:

224

AN XY:

517220

show subpopulations

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

African (AFR)

AF:

0.000327

AC:

AN:

21380

American (AMR)

AF:

0.00153

AC:

AN:

7844

Ashkenazi Jewish (ASJ)

AF:

0.000555

AC:

AN:

12614

East Asian (EAS)

AF:

0.000587

AC:

AN:

23842

South Asian (SAS)

AF:

0.000753

AC:

AN:

25236

European-Finnish (FIN)

AF:

0.000557

AC:

AN:

25126

Middle Eastern (MID)

AF:

0.000703

AC:

AN:

2844

European-Non Finnish (NFE)

AF:

0.000340

AC:

310

AN:

913088

Other (OTH)

AF:

0.000530

AC:

AN:

41540

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.372

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000193

AC:

AN:

144946

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

AN XY:

70594

show subpopulations

African (AFR)

AF:

0.000199

AC:

AN:

40198

American (AMR)

AF:

0.000273

AC:

AN:

14664

Ashkenazi Jewish (ASJ)

AF:

0.000888

AC:

AN:

3380

East Asian (EAS)

AF:

0.000837

AC:

AN:

4778

South Asian (SAS)

AF:

0.00

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000123

AC:

AN:

65128

Other (OTH)

AF:

0.000493

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.6

Mutation Taster

=82/18

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over