NM_004473.4:c.-131G>C

Variant names:

• chr9-97853784-G-C
• rs1867280
• NM_004473.4:c.-131G>C

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.-131G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 847,778 control chromosomes in the GnomAD database, including 166,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30774 hom., cov: 34)
  • Exomes 𝑓: 0.62 (136195 hom.)
• Consequence: FOXE1 NM_004473.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.249
• Publications: 12 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 9-97853784-G-C is Benign according to our data. Variant chr9-97853784-G-C is described in ClinVar as Benign. ClinVar VariationId is 1294056.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.-131G>C		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.-131G>C		5_prime_UTR_variant	Exon 1 of 1	6	NM_004473.4	ENSP00000364265.3

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96219 AN: 151936 Hom.: 30749 Cov.: 34

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.885

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: 0.623 AC: 433223 AN: 695732 Hom.: 136195 Cov.: 9 AF XY: 0.622 AC XY: 208981 AN XY: 335828

African (AFR) AF: 0.672 AC: 10006 AN: 14884

American (AMR) AF: 0.644 AC: 4481 AN: 6958

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 5055 AN: 10540

East Asian (EAS) AF: 0.874 AC: 19161 AN: 21926

South Asian (SAS) AF: 0.629 AC: 7720 AN: 12272

European-Finnish (FIN) AF: 0.637 AC: 13079 AN: 20536

Middle Eastern (MID) AF: 0.535 AC: 1107 AN: 2068

European-Non Finnish (NFE) AF: 0.614 AC: 354032 AN: 576706

Other (OTH) AF: 0.623 AC: 18582 AN: 29842

GnomAD4 genome AF: 0.633 AC: 96278 AN: 152046 Hom.: 30774 Cov.: 34 AF XY: 0.638 AC XY: 47403 AN XY: 74346

African (AFR) AF: 0.662 AC: 27474 AN: 41488

American (AMR) AF: 0.651 AC: 9959 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1658 AN: 3470

East Asian (EAS) AF: 0.886 AC: 4551 AN: 5136

South Asian (SAS) AF: 0.633 AC: 3054 AN: 4828

European-Finnish (FIN) AF: 0.640 AC: 6777 AN: 10594

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

European-Non Finnish (NFE) AF: 0.603 AC: 40932 AN: 67932

Other (OTH) AF: 0.629 AC: 1328 AN: 2112

Alfa AF: 0.620 Hom.: 3649

Bravo AF: 0.637

Asia WGS AF: 0.718 AC: 2494 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.4
DANN	Benign	0.73
PhyloP100		0.25
Mutation Taster		=299/1	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: rs1867280; hg19: chr9-100616066;