9-97854412-TGCCGCAGCCGCC-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_004473.4(FOXE1):c.504_515del(p.Ala176_Ala179del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,192,314 control chromosomes in the GnomAD database, including 55 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 0)
  • Exomes 𝑓: 0.0064 (37 hom.)
• Consequence: FOXE1 NM_004473.4 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.56

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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004473.4
• BP6: Variant 9-97854412-TGCCGCAGCCGCC-T is Benign according to our data. Variant chr9-97854412-TGCCGCAGCCGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 3044967.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-97854412-TGCCGCAGCCGCC-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.011 (1035/94260) while in subpopulation AMR AF= 0.0228 (218/9582). AF 95% confidence interval is 0.0203. There are 18 homozygotes in gnomad4. There are 526 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXE1	NM_004473.4	c.504_515del	p.Ala176_Ala179del	inframe_deletion	1/1	ENST00000375123.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXE1	ENST00000375123.5	c.504_515del	p.Ala176_Ala179del	inframe_deletion	1/1		NM_004473.4	P1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1034 AN: 94190 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.00790

Gnomad EAS AF: 0.00515

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.00538

Gnomad NFE AF: 0.00829

Gnomad OTH AF: 0.00559

GnomAD3 exomes AF: 0.0106 AC: 509 AN: 47978 Hom.: 7 AF XY: 0.0106 AC XY: 308 AN XY: 28938

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.00459

Gnomad EAS exome AF: 0.000424

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.00824

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.00642 AC: 7054 AN: 1098054 Hom.: 37 AF XY: 0.00651 AC XY: 3482 AN XY: 534802

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.0189

Gnomad4 ASJ exome AF: 0.00578

Gnomad4 EAS exome AF: 0.000735

Gnomad4 SAS exome AF: 0.00836

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.00616

Gnomad4 OTH exome AF: 0.00749

GnomAD4 genome AF: 0.0110 AC: 1035 AN: 94260 Hom.: 18 Cov.: 0 AF XY: 0.0117 AC XY: 526 AN XY: 45066

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.00790

Gnomad4 EAS AF: 0.00517

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0232

Gnomad4 NFE AF: 0.00831

Gnomad4 OTH AF: 0.00551

Alfa AF: 0.00352 Hom.: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FOXE1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762571620; hg19: chr9-100616694;