9-97854199-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004473.4(FOXE1):c.285A>G(p.Lys95=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,612,922 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (18 hom.)
• Consequence: FOXE1 NM_004473.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.205

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 9-97854199-A-G is Benign according to our data. Variant chr9-97854199-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 435238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-97854199-A-G is described in Lovd as [Benign]. Variant chr9-97854199-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.205 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXE1	NM_004473.4	c.285A>G	p.Lys95=	synonymous_variant	1/1	ENST00000375123.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXE1	ENST00000375123.5	c.285A>G	p.Lys95=	synonymous_variant	1/1		NM_004473.4	P1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 151694 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00267 AC: 668 AN: 250320 Hom.: 4 AF XY: 0.00263 AC XY: 357 AN XY: 135674

Gnomad AFR exome AF: 0.000809

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00412

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00353 AC: 5154 AN: 1461118 Hom.: 18 Cov.: 31 AF XY: 0.00337 AC XY: 2447 AN XY: 726878

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00183

Gnomad4 NFE exome AF: 0.00423

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00263 AC: 400 AN: 151804 Hom.: 3 Cov.: 33 AF XY: 0.00256 AC XY: 190 AN XY: 74194

Gnomad4 AFR AF: 0.000651

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00181

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00347 Hom.: 0

Bravo AF: 0.00248

Asia WGS AF: 0.000290 AC: 1 AN: 3458

EpiCase AF: 0.00403

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	FOXE1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2017	- -

Bamforth-Lazarus syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Jun 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	8.9
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs139551528; hg19: chr9-100616481;