Genetic Variant FOXE1:c.-248C>A (chr9-97853667-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004473.4(FOXE1):c.-248C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 359,054 control chromosomes in the GnomAD database, including 72,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 30761 hom., cov: 32)

Exomes 𝑓: 0.63 ( 41821 hom. )

Consequence

FOXE1
NM_004473.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.416

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 9-97853667-C-A is Benign according to our data. Variant chr9-97853667-C-A is described in ClinVar as [Benign]. Clinvar id is 1253567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE1	NM_004473.4 link	c.-248C>A		5_prime_UTR_variant	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 link	c.-248C>A		5_prime_UTR_variant	Exon 1 of 1		NM_004473.4	ENSP00000364265.3		O00358

Frequencies

GnomAD3 genomes

AF:

0.633

AC:

96190

AN:

151916

Hom.:

30734

Cov.:

show subpopulations

Gnomad AFR

AF:

0.662

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.651

Gnomad ASJ

AF:

0.478

Gnomad EAS

AF:

0.885

Gnomad SAS

AF:

0.634

Gnomad FIN

AF:

0.640

Gnomad MID

AF:

0.612

Gnomad NFE

AF:

0.602

Gnomad OTH

AF:

0.629

GnomAD4 exome

AF:

0.630

AC:

130329

AN:

207022

Hom.:

41821

Cov.:

AF XY:

0.626

AC XY:

66295

AN XY:

105864

show subpopulations

African (AFR)

AF:

0.665

AC:

3694

AN:

5556

American (AMR)

AF:

0.639

AC:

3800

AN:

5950

Ashkenazi Jewish (ASJ)

AF:

0.475

AC:

3411

AN:

7178

East Asian (EAS)

AF:

0.872

AC:

16234

AN:

18624

South Asian (SAS)

AF:

0.653

AC:

1343

AN:

2056

European-Finnish (FIN)

AF:

0.635

AC:

12137

AN:

19116

Middle Eastern (MID)

AF:

0.530

AC:

550

AN:

1038

European-Non Finnish (NFE)

AF:

0.602

AC:

80848

AN:

134258

Other (OTH)

AF:

0.628

AC:

8312

AN:

13246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2257

4515

6772

9030

11287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.633

AC:

96253

AN:

152032

Hom.:

30761

Cov.:

AF XY:

0.638

AC XY:

47380

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.662

AC:

27460

AN:

41476

American (AMR)

AF:

0.652

AC:

9966

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.478

AC:

1657

AN:

3470

East Asian (EAS)

AF:

0.886

AC:

4548

AN:

5132

South Asian (SAS)

AF:

0.633

AC:

3054

AN:

4828

European-Finnish (FIN)

AF:

0.640

AC:

6774

AN:

10588

Middle Eastern (MID)

AF:

0.614

AC:

178

AN:

290

European-Non Finnish (NFE)

AF:

0.602

AC:

40919

AN:

67928

Other (OTH)

AF:

0.628

AC:

1328

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1843

3686

5530

7373

9216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.618

Hom.:

4180

Bravo

AF:

0.637

Asia WGS

AF:

0.718

AC:

2498

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.4

(source)

DANN

Benign

0.68

PromoterAI

0.17

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr9-97853667-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over