rs538912281

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004473.4(FOXE1):c.743C>G(p.Ala248Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,402,532 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0043 ( 11 hom. )

Consequence

FOXE1
NM_004473.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:3

Conservation

PhyloP100: -0.495

Publications

16 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074782073).

BP6

Variant 9-97854657-C-G is Benign according to our data. Variant chr9-97854657-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 208453.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.743C>G	p.Ala248Gly	missense	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.743C>G	p.Ala248Gly	missense	Exon 1 of 1	ENSP00000364265.3	O00358

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

429

AN:

151700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000846

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000860

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00491

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00197

AC:

AN:

30012

AF XY:

0.00188

show subpopulations

Gnomad AFR exome

AF:

0.00220

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00336

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000526

Gnomad NFE exome

AF:

0.00318

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00431

AC:

5396

AN:

1250724

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

2642

AN XY:

613256

show subpopulations

African (AFR)

AF:

0.000455

AC:

AN:

24200

American (AMR)

AF:

0.00185

AC:

AN:

14562

Ashkenazi Jewish (ASJ)

AF:

0.00425

AC:

AN:

18816

East Asian (EAS)

AF:

0.00

AC:

AN:

27864

South Asian (SAS)

AF:

0.000297

AC:

AN:

60564

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

30404

Middle Eastern (MID)

AF:

0.00442

AC:

AN:

3620

European-Non Finnish (NFE)

AF:

0.00494

AC:

5037

AN:

1019394

Other (OTH)

AF:

0.00326

AC:

167

AN:

51300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

313

625

938

1250

1563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

208

416

624

832

1040

<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:

0.00283

AC:

429

AN:

151808

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

211

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.000844

AC:

AN:

41488

American (AMR)

AF:

0.00223

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000860

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00491

AC:

333

AN:

67864

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

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:

0.000479

Hom.:

Bravo

AF:

0.00266

Asia WGS

AF:

0.000295

AC:

AN:

3410

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bamforth-Lazarus syndrome (2)

Bamforth-Lazarus syndrome;C4225293:Thyroid cancer, nonmedullary, 4 (1)

not provided (1)

not specified (1)

Thyroid cancer, nonmedullary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.34

PhyloP100

-0.49

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.41

REVEL

Pathogenic

0.66

Sift

Benign

0.14

Sift4G

Benign

0.29

Varity_R

0.063

gMVP

0.23

Mutation Taster

=86/14

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