chr9-97854418-AGCCGCCGCCGCC-A

Variant names:

• chr9-97854418-AGCCGCCGCCGCC-A
• rs71369530
• NM_004473.4:c.526_537delGCCGCCGCCGCC

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_004473.4(FOXE1):​c.526_537delGCCGCCGCCGCC​(p.Ala176_Ala179del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00658 in 1,219,990 control chromosomes in the GnomAD database, including 40 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 0)
  • Exomes 𝑓: 0.0067 (35 hom.)
• Consequence: FOXE1 NM_004473.4 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.03
• Publications: 21 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004473.4
• BP6: Variant 9-97854418-AGCCGCCGCCGCC-A is Benign according to our data. Variant chr9-97854418-AGCCGCCGCCGCC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 522197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.526_537delGCCGCCGCCGCC	p.Ala176_Ala179del	conservative_inframe_deletion	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.526_537delGCCGCCGCCGCC	p.Ala176_Ala179del	conservative_inframe_deletion	Exon 1 of 1	ENSP00000364265.3	O00358

Frequencies

GnomAD3 genomes AF: 0.00593 AC: 859 AN: 144844 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.00197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00778

Gnomad ASJ AF: 0.0157

Gnomad EAS AF: 0.000626

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.00720

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00368 AC: 45 AN: 12212 AF XY: 0.00374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00922

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00667 AC: 7173 AN: 1075046 Hom.: 35 AF XY: 0.00675 AC XY: 3497 AN XY: 518024

African (AFR) AF: 0.00131 AC: 28 AN: 21396

American (AMR) AF: 0.00864 AC: 68 AN: 7870

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 190 AN: 12636

East Asian (EAS) AF: 0.000126 AC: 3 AN: 23842

South Asian (SAS) AF: 0.00348 AC: 88 AN: 25278

European-Finnish (FIN) AF: 0.0110 AC: 277 AN: 25218

Middle Eastern (MID) AF: 0.0144 AC: 41 AN: 2850

European-Non Finnish (NFE) AF: 0.00674 AC: 6165 AN: 914354

Other (OTH) AF: 0.00752 AC: 313 AN: 41602

GnomAD4 genome AF: 0.00593 AC: 859 AN: 144944 Hom.: 5 Cov.: 0 AF XY: 0.00603 AC XY: 426 AN XY: 70594

African (AFR) AF: 0.00197 AC: 79 AN: 40194

American (AMR) AF: 0.00778 AC: 114 AN: 14662

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 53 AN: 3380

East Asian (EAS) AF: 0.000628 AC: 3 AN: 4780

South Asian (SAS) AF: 0.00170 AC: 8 AN: 4706

European-Finnish (FIN) AF: 0.0112 AC: 101 AN: 9014

Middle Eastern (MID) AF: 0.0182 AC: 5 AN: 274

European-Non Finnish (NFE) AF: 0.00720 AC: 469 AN: 65132

Other (OTH) AF: 0.0133 AC: 27 AN: 2028

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Bamforth-Lazarus syndrome (1)
-	-	1	Bamforth-Lazarus syndrome;C4225293:Thyroid cancer, nonmedullary, 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=176/24	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71369530; hg19: chr9-100616700;