rs1867277

Variant names:

• chr9-97853632-A-G
• rs1867277
• NM_004473.4:c.-283A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004473.4(FOXE1):​c.-283A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 343,252 control chromosomes in the GnomAD database, including 69,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30797 hom., cov: 33)
  • Exomes 𝑓: 0.63 (38383 hom.)
• Consequence: FOXE1 NM_004473.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08
• Publications: 80 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-97853632-A-G is Benign according to our data. Variant chr9-97853632-A-G is described in ClinVar as Benign. ClinVar VariationId is 1297302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXE1	NM_004473.4	c.-283A>G		5_prime_UTR_variant	Exon 1 of 1	ENST00000375123.5	NP_004464.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXE1	ENST00000375123.5	c.-283A>G		5_prime_UTR_variant	Exon 1 of 1	6	NM_004473.4	ENSP00000364265.3

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96259 AN: 151980 Hom.: 30772 Cov.: 33

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.629

GnomAD4 exome AF: 0.627 AC: 119889 AN: 191158 Hom.: 38383 Cov.: 2 AF XY: 0.624 AC XY: 61126 AN XY: 97906

African (AFR) AF: 0.659 AC: 3433 AN: 5208

American (AMR) AF: 0.637 AC: 3505 AN: 5502

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 3188 AN: 6708

East Asian (EAS) AF: 0.872 AC: 14880 AN: 17070

South Asian (SAS) AF: 0.653 AC: 1269 AN: 1944

European-Finnish (FIN) AF: 0.634 AC: 11341 AN: 17878

Middle Eastern (MID) AF: 0.530 AC: 515 AN: 972

European-Non Finnish (NFE) AF: 0.599 AC: 74075 AN: 123610

Other (OTH) AF: 0.626 AC: 7683 AN: 12266

GnomAD4 genome AF: 0.633 AC: 96319 AN: 152094 Hom.: 30797 Cov.: 33 AF XY: 0.638 AC XY: 47411 AN XY: 74348

African (AFR) AF: 0.662 AC: 27484 AN: 41506

American (AMR) AF: 0.652 AC: 9959 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1658 AN: 3472

East Asian (EAS) AF: 0.887 AC: 4565 AN: 5148

South Asian (SAS) AF: 0.633 AC: 3055 AN: 4826

European-Finnish (FIN) AF: 0.640 AC: 6771 AN: 10580

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.603 AC: 40951 AN: 67964

Other (OTH) AF: 0.628 AC: 1328 AN: 2114

Alfa AF: 0.623 Hom.: 6880

Bravo AF: 0.637

Asia WGS AF: 0.719 AC: 2499 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22282540, 19730683, 26202972, 31395865) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.4
DANN	Benign	0.41
PhyloP100		-1.1
PromoterAI		-0.13	Neutral
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs1867277; hg19: chr9-100615914;