9-97854140-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_004473.4(FOXE1):​c.226C>G​(p.Leu76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FOXE1
NM_004473.4 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.172
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a DNA_binding_region Fork-head (size 94) in uniprot entity FOXE1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_004473.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXE1NM_004473.4 linkc.226C>G p.Leu76Val missense_variant Exon 1 of 1 ENST00000375123.5 NP_004464.2 O00358

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXE1ENST00000375123.5 linkc.226C>G p.Leu76Val missense_variant Exon 1 of 1 6 NM_004473.4 ENSP00000364265.3 O00358

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248634
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135162
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460570
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726638
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.000111
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 23, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: FOXE1 c.226C>G (p.Leu76Val) results in a conservative amino acid change located in the Fork head domain (IPR001766) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248634 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.226C>G in individuals affected with Bamforth-Lazarus Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.045
FATHMM_MKL
Benign
0.61
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Uncertain
2.4
M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-2.8
D
REVEL
Pathogenic
0.73
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0090
D
Polyphen
0.99
D
Vest4
0.71
MutPred
0.93
Gain of glycosylation at T75 (P = 0.1355);
MVP
0.92
ClinPred
0.97
D
GERP RS
2.9
Varity_R
0.72
gMVP
0.70

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.

Other links and lift over

dbSNP: rs1200038300; hg19: chr9-100616422; API