9-97854657-C-A

Variant names:

• chr9-97854657-C-A
• rs538912281
• NM_004473.4:c.743C>A
• FOXE1 p.Ala248Asp

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004473.4(FOXE1):​c.743C>A​(p.Ala248Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,402,440 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: FOXE1 NM_004473.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.495
• Publications: 16 publications found

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)

ACMG classification

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=0.18433079).

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>A	p.Ala248Asp	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>A	p.Ala248Asp	missense	Exon 1 of 1	ENSP00000364265.3	O00358

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151700 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000240 AC: 3 AN: 1250740 Hom.: 0 Cov.: 50 AF XY: 0.00000326 AC XY: 2 AN XY: 613262

African (AFR) AF: 0.00 AC: 0 AN: 24200

American (AMR) AF: 0.00 AC: 0 AN: 14562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18818

East Asian (EAS) AF: 0.00 AC: 0 AN: 27864

South Asian (SAS) AF: 0.00 AC: 0 AN: 60564

European-Finnish (FIN) AF: 0.0000329 AC: 1 AN: 30404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3622

European-Non Finnish (NFE) AF: 0.00000196 AC: 2 AN: 1019406

Other (OTH) AF: 0.00 AC: 0 AN: 51300

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151700 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41370

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67874

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.49
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.35
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Varity_R		0.17
gMVP		0.41
Mutation Taster		=77/23	polymorphism

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.

Other links and lift over

dbSNP: rs538912281;

hg19: chr9-100616939;