rs1867278

Variant names:

• chr9-97853667-C-A
• rs1867278
• NM_004473.4:c.-248C>A

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.-248C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 359,054 control chromosomes in the GnomAD database, including 72,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30761 hom., cov: 32)
  • Exomes 𝑓: 0.63 (41821 hom.)
• Consequence: FOXE1 NM_004473.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.416
• Publications: 19 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 9-97853667-C-A is Benign according to our data. Variant chr9-97853667-C-A is described in ClinVar as Benign. ClinVar VariationId is 1253567.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.

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.-248C>A		5_prime_UTR	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.-248C>A		5_prime_UTR	Exon 1 of 1	ENSP00000364265.3

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96190 AN: 151916 Hom.: 30734 Cov.: 32

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.405

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: 0.612

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.629

GnomAD4 exome AF: 0.630 AC: 130329 AN: 207022 Hom.: 41821 Cov.: 3 AF XY: 0.626 AC XY: 66295 AN XY: 105864

African (AFR) AF: 0.665 AC: 3694 AN: 5556

American (AMR) AF: 0.639 AC: 3800 AN: 5950

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 3411 AN: 7178

East Asian (EAS) AF: 0.872 AC: 16234 AN: 18624

South Asian (SAS) AF: 0.653 AC: 1343 AN: 2056

European-Finnish (FIN) AF: 0.635 AC: 12137 AN: 19116

Middle Eastern (MID) AF: 0.530 AC: 550 AN: 1038

European-Non Finnish (NFE) AF: 0.602 AC: 80848 AN: 134258

Other (OTH) AF: 0.628 AC: 8312 AN: 13246

GnomAD4 genome AF: 0.633 AC: 96253 AN: 152032 Hom.: 30761 Cov.: 32 AF XY: 0.638 AC XY: 47380 AN XY: 74320

African (AFR) AF: 0.662 AC: 27460 AN: 41476

American (AMR) AF: 0.652 AC: 9966 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1657 AN: 3470

East Asian (EAS) AF: 0.886 AC: 4548 AN: 5132

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

European-Finnish (FIN) AF: 0.640 AC: 6774 AN: 10588

Middle Eastern (MID) AF: 0.614 AC: 178 AN: 290

European-Non Finnish (NFE) AF: 0.602 AC: 40919 AN: 67928

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

Alfa AF: 0.618 Hom.: 4180

Bravo AF: 0.637

Asia WGS AF: 0.718 AC: 2498 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.4
DANN	Benign	0.68
PhyloP100		-0.42
PromoterAI		0.17	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: rs1867278; hg19: chr9-100615949;