Genetic Variant FOXE1:p.Ala179dup (chr9-97854418-A-AGCC) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_004473.4(FOXE1):c.535_537dupGCC(p.Ala179dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.017 ( 22 hom., cov: 0)

Exomes 𝑓: 0.012 ( 57 hom. )

Consequence

FOXE1
NM_004473.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign no assertion criteria provided B:2

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: 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: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004473.4

BP6

Variant 9-97854418-A-AGCC is Benign according to our data. Variant chr9-97854418-A-AGCC is described in CliVar as Benign. Clinvar id is 1284456.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-97854418-A-AGCC is described in CliVar as Benign. Clinvar id is 1284456.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0174 (2523/144948) while in subpopulation AMR AF = 0.0222 (326/14664). AF 95% confidence interval is 0.0202. There are 22 homozygotes in GnomAd4. There are 1307 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE1	NM_004473.4 link	c.535_537dupGCC	p.Ala179dup	conservative_inframe_insertion	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.535_537dupGCC	p.Ala179dup	conservative_inframe_insertion	Exon 1 of 1	6	NM_004473.4	ENSP00000364265.3		O00358

Frequencies

GnomAD3 genomes

AF:

0.0174

AC:

2523

AN:

144848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.0336

Gnomad AMR

AF:

0.0223

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00616

Gnomad FIN

AF:

0.0207

Gnomad MID

AF:

0.0203

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.0214

GnomAD2 exomes

AF:

0.00295

AC:

AN:

12212

AF XY:

0.00254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0108

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0124

AC:

13302

AN:

1073494

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

6298

AN XY:

517268

show subpopulations

African (AFR)

AF:

0.0181

AC:

385

AN:

21316

American (AMR)

AF:

0.00930

AC:

AN:

7846

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

249

AN:

12484

East Asian (EAS)

AF:

0.000126

AC:

AN:

23838

South Asian (SAS)

AF:

0.00526

AC:

133

AN:

25276

European-Finnish (FIN)

AF:

0.0123

AC:

307

AN:

25060

Middle Eastern (MID)

AF:

0.0201

AC:

AN:

2834

European-Non Finnish (NFE)

AF:

0.0127

AC:

11636

AN:

913358

Other (OTH)

AF:

0.0111

AC:

459

AN:

41482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

597

1194

1792

2389

2986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

554

1108

1662

2216

2770

<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:

0.0174

AC:

2523

AN:

144948

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1307

AN XY:

70600

show subpopulations

African (AFR)

AF:

0.0194

AC:

778

AN:

40192

American (AMR)

AF:

0.0222

AC:

326

AN:

14664

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

103

AN:

3380

East Asian (EAS)

AF:

0.00

AC:

AN:

4780

South Asian (SAS)

AF:

0.00637

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.0207

AC:

187

AN:

9020

Middle Eastern (MID)

AF:

0.0182

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0157

AC:

1025

AN:

65130

Other (OTH)

AF:

0.0212

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

114

228

343

457

571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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: Benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.6

Mutation Taster

=78/22

polymorphism

(source)

Splicing

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

Publications

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9-97854418-AGCCGCCGCCGCCGCCGCCGCCGCCGCC-AGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

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