Genetic Variant NM_004473.4:c.520_537delGCCGCCGCCGCCGCCGCC (chr9-97854418-AGCCGCCGCCGCCGCCGCC-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_004473.4(FOXE1):c.520_537delGCCGCCGCCGCCGCCGCC(p.Ala174_Ala179del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000244 in 1,220,050 control chromosomes in the GnomAD database, including 4 homozygotes. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00023 ( 4 hom. )

Consequence

FOXE1
NM_004473.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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 -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004473.4

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE1	NM_004473.4 link	c.520_537delGCCGCCGCCGCCGCCGCC	p.Ala174_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.520_537delGCCGCCGCCGCCGCCGCC	p.Ala174_Ala179del	conservative_inframe_deletion	Exon 1 of 1	6	NM_004473.4	ENSP00000364265.3		O00358

Frequencies

GnomAD3 genomes

AF:

0.000331

AC:

AN:

144856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000399

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00116

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000626

Gnomad SAS

AF:

0.000849

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000123

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000232

AC:

249

AN:

1075094

Hom.:

AF XY:

0.000270

AC XY:

140

AN XY:

518060

show subpopulations

African (AFR)

AF:

0.000327

AC:

AN:

21398

American (AMR)

AF:

0.000889

AC:

AN:

7872

Ashkenazi Jewish (ASJ)

AF:

0.000475

AC:

AN:

12636

East Asian (EAS)

AF:

0.000252

AC:

AN:

23844

South Asian (SAS)

AF:

0.000910

AC:

AN:

25278

European-Finnish (FIN)

AF:

0.0000793

AC:

AN:

25218

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

2850

European-Non Finnish (NFE)

AF:

0.000187

AC:

171

AN:

914394

Other (OTH)

AF:

0.000553

AC:

AN:

41604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

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:

0.000338

AC:

AN:

144956

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

AN XY:

70600

show subpopulations

African (AFR)

AF:

0.000398

AC:

AN:

40198

American (AMR)

AF:

0.00116

AC:

AN:

14664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3380

East Asian (EAS)

AF:

0.000837

AC:

AN:

4780

South Asian (SAS)

AF:

0.000850

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000123

AC:

AN:

65132

Other (OTH)

AF:

0.00

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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 v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.0

Mutation Taster

=168/32

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

Computational scores

Splicing

Publications

Other links and lift over