rs3021526

Variant names:

• chr9-97854739-C-T
• rs3021526
• NM_004473.4:c.825C>T
• FOXE1 p.Ser275Ser

Your query was ambiguous. Multiple possible variants found:

• chr9-97854739-C-T
• chr9-97854739-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004473.4(FOXE1):​c.825C>T​(p.Ser275Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,456,554 control chromosomes in the GnomAD database, including 282,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30736 hom., cov: 34)
  • Exomes 𝑓: 0.62 (251846 hom.)
• Consequence: FOXE1 NM_004473.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.67
• Publications: 24 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-97854739-C-T is Benign according to our data. Variant chr9-97854739-C-T is described in ClinVar as Benign. ClinVar VariationId is 95098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 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.825C>T	p.Ser275Ser	synonymous	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.825C>T	p.Ser275Ser	synonymous	Exon 1 of 1	ENSP00000364265.3	O00358

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96098 AN: 151754 Hom.: 30711 Cov.: 34

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.628

GnomAD2 exomes AF: 0.672 AC: 40853 AN: 60772 AF XY: 0.667

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.898

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.619 AC: 807716 AN: 1304692 Hom.: 251846 Cov.: 57 AF XY: 0.619 AC XY: 395965 AN XY: 639986

African (AFR) AF: 0.668 AC: 17304 AN: 25920

American (AMR) AF: 0.679 AC: 15647 AN: 23030

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 9732 AN: 19910

East Asian (EAS) AF: 0.878 AC: 28347 AN: 32296

South Asian (SAS) AF: 0.622 AC: 41459 AN: 66700

European-Finnish (FIN) AF: 0.639 AC: 20017 AN: 31344

Middle Eastern (MID) AF: 0.533 AC: 2015 AN: 3780

European-Non Finnish (NFE) AF: 0.611 AC: 639634 AN: 1047502

Other (OTH) AF: 0.619 AC: 33561 AN: 54210

GnomAD4 genome AF: 0.633 AC: 96157 AN: 151862 Hom.: 30736 Cov.: 34 AF XY: 0.638 AC XY: 47349 AN XY: 74268

African (AFR) AF: 0.662 AC: 27464 AN: 41472

American (AMR) AF: 0.651 AC: 9930 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1656 AN: 3470

East Asian (EAS) AF: 0.885 AC: 4560 AN: 5150

South Asian (SAS) AF: 0.633 AC: 3055 AN: 4828

European-Finnish (FIN) AF: 0.640 AC: 6738 AN: 10520

Middle Eastern (MID) AF: 0.617 AC: 179 AN: 290

European-Non Finnish (NFE) AF: 0.602 AC: 40885 AN: 67862

Other (OTH) AF: 0.628 AC: 1323 AN: 2108

Alfa AF: 0.621 Hom.: 3236

Bravo AF: 0.637

Asia WGS AF: 0.716 AC: 2471 AN: 3446

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Bamforth-Lazarus syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.4
DANN	Benign	0.89
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs3021526;

hg19: chr9-100617021;

COSMIC: COSV108219210;