Genetic Variant FOXE1:c.-644A>G (chr9-97853271-A-G) – 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.-644A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 152,308 control chromosomes in the GnomAD database, including 30,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 30787 hom., cov: 33)

Exomes 𝑓: 0.64 ( 55 hom. )

Consequence

FOXE1
NM_004473.4 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.948

Publications

4 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 links:

PTCSC2 (HGNC:44086): (papillary thyroid carcinoma susceptibility candidate 2)

PTCSC2 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=-0.86).

BP6

Variant 9-97853271-A-G is Benign according to our data. Variant chr9-97853271-A-G is described in ClinVar as Benign. ClinVar VariationId is 1294066.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.

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.-644A>G		5_prime_UTR	Exon 1 of 1	NP_004464.2
	PTCSC2	NR_147055.1		n.-191T>C		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FOXE1	ENST00000375123.5	TSL:6 MANE Select	c.-644A>G	5_prime_UTR	Exon 1 of 1	ENSP00000364265.3	O00358
PTCSC2	ENST00000649253.2		n.-191T>C	upstream_gene	N/A
PTCSC2	ENST00000649461.1		n.-191T>C	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.633

AC:

96231

AN:

151926

Hom.:

30762

Cov.:

show subpopulations

Gnomad AFR

AF:

0.663

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.651

Gnomad ASJ

AF:

0.480

Gnomad EAS

AF:

0.886

Gnomad SAS

AF:

0.634

Gnomad FIN

AF:

0.640

Gnomad MID

AF:

0.619

Gnomad NFE

AF:

0.603

Gnomad OTH

AF:

0.629

GnomAD4 exome

AF:

0.637

AC:

172

AN:

270

Hom.:

Cov.:

AF XY:

0.668

AC XY:

139

AN XY:

208

show subpopulations

African (AFR)

AF:

0.625

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.875

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AF:

0.667

AC:

AN:

European-Non Finnish (NFE)

AF:

0.632

AC:

139

AN:

220

Other (OTH)

AF:

0.722

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.633

AC:

96291

AN:

152038

Hom.:

30787

Cov.:

AF XY:

0.638

AC XY:

47395

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.662

AC:

27485

AN:

41500

American (AMR)

AF:

0.652

AC:

9961

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.480

AC:

1661

AN:

3464

East Asian (EAS)

AF:

0.887

AC:

4546

AN:

5128

South Asian (SAS)

AF:

0.633

AC:

3053

AN:

4824

European-Finnish (FIN)

AF:

0.640

AC:

6769

AN:

10584

Middle Eastern (MID)

AF:

0.621

AC:

180

AN:

290

European-Non Finnish (NFE)

AF:

0.603

AC:

40942

AN:

67944

Other (OTH)

AF:

0.628

AC:

1326

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1843

3686

5529

7372

9215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.570

Hom.:

3670

Bravo

AF:

0.637

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.7

(source)

DANN

Benign

0.69

PhyloP100

-0.95

PromoterAI

-0.025

Neutral

(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

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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