9-97853927-A-G

Position:

• chr9-97853927-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004473.4(FOXE1):​c.13A>G​(p.Ser5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXE1 NM_004473.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.999

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21897721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXE1	NM_004473.4	c.13A>G	p.Ser5Gly	missense_variant	1/1	ENST00000375123.5	NP_004464.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXE1	ENST00000375123.5	c.13A>G	p.Ser5Gly	missense_variant	1/1	6	NM_004473.4	ENSP00000364265.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1145046 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 550684

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.13A>G (p.S5G) alteration is located in exon 1 (coding exon 1) of the FOXE1 gene. This alteration results from a A to G substitution at nucleotide position 13, causing the serine (S) at amino acid position 5 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.24
Sift	Uncertain	0.010	D
Sift4G	Benign	0.096	T
Polyphen		0.067	B
Vest4		0.093
MutPred		0.21		Loss of glycosylation at S5 (P = 0.0038);
MVP		0.71
ClinPred		0.72	D
GERP RS		2.8
Varity_R		0.13
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-100616209;