Genetic Variant FOXE1:p.Ala248Val (chr9-97854657-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004473.4(FOXE1):c.743C>T(p.Ala248Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000008 in 1,250,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A248G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

FOXE1
NM_004473.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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: 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18972334).

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>T	p.Ala248Val	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>T	p.Ala248Val	missense	Exon 1 of 1	ENSP00000364265.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.00e-7

AC:

AN:

1250740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

613262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24200

American (AMR)

AF:

0.00

AC:

AN:

14562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18818

East Asian (EAS)

AF:

0.00

AC:

AN:

27864

South Asian (SAS)

AF:

0.00

AC:

AN:

60564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3622

European-Non Finnish (NFE)

AF:

9.81e-7

AC:

AN:

1019406

Other (OTH)

AF:

0.00

AC:

AN:

51300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.90

PhyloP100

-0.49

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.35

Sift

Benign

0.035

Sift4G

Benign

0.40

Polyphen

0.037

Vest4

0.20

MutPred

0.35

Gain of loop (P = 0.069)

MVP

0.69

ClinPred

0.45

GERP RS

2.6

Varity_R

0.064

gMVP

0.33

Mutation Taster

=85/15

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over