9-97854418-AGCCGCC-A

Variant names:

• chr9-97854418-AGCCGCC-A
• rs71369530
• NM_004473.4:c.532_537delGCCGCC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_004473.4(FOXE1):​c.532_537delGCCGCC​(p.Ala178_Ala179del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,218,904 control chromosomes in the GnomAD database, including 240,692 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (34316 hom., cov: 0)
  • Exomes 𝑓: 0.62 (206376 hom.)
• Consequence: FOXE1 NM_004473.4 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.56
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004473.4
• BP6: Variant 9-97854418-AGCCGCC-A is Benign according to our data. Variant chr9-97854418-AGCCGCC-A is described in ClinVar as Benign. ClinVar VariationId is 95097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.955 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.532_537delGCCGCC	p.Ala178_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.532_537delGCCGCC	p.Ala178_Ala179del	conservative_inframe_deletion	Exon 1 of 1	ENSP00000364265.3	O00358

Frequencies

GnomAD3 genomes AF: 0.684 AC: 98926 AN: 144700 Hom.: 34290 Cov.: 0

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.690

GnomAD2 exomes AF: 0.199 AC: 2426 AN: 12212 AF XY: 0.195

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.621 AC: 667120 AN: 1074104 Hom.: 206376 AF XY: 0.619 AC XY: 320603 AN XY: 517590

African (AFR) AF: 0.787 AC: 16835 AN: 21384

American (AMR) AF: 0.626 AC: 4911 AN: 7850

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 7898 AN: 12620

East Asian (EAS) AF: 0.946 AC: 22542 AN: 23832

South Asian (SAS) AF: 0.623 AC: 15719 AN: 25250

European-Finnish (FIN) AF: 0.587 AC: 14750 AN: 25124

Middle Eastern (MID) AF: 0.584 AC: 1661 AN: 2842

European-Non Finnish (NFE) AF: 0.609 AC: 556084 AN: 913670

Other (OTH) AF: 0.643 AC: 26720 AN: 41532

GnomAD4 genome AF: 0.684 AC: 98989 AN: 144800 Hom.: 34316 Cov.: 0 AF XY: 0.686 AC XY: 48360 AN XY: 70522

African (AFR) AF: 0.787 AC: 31614 AN: 40146

American (AMR) AF: 0.684 AC: 10018 AN: 14654

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2116 AN: 3380

East Asian (EAS) AF: 0.978 AC: 4676 AN: 4780

South Asian (SAS) AF: 0.685 AC: 3218 AN: 4700

European-Finnish (FIN) AF: 0.615 AC: 5539 AN: 9002

Middle Eastern (MID) AF: 0.723 AC: 198 AN: 274

European-Non Finnish (NFE) AF: 0.612 AC: 39834 AN: 65070

Other (OTH) AF: 0.689 AC: 1394 AN: 2024

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Bamforth-Lazarus syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=192/8	polymorphism (auto)

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; COSMIC: COSV64299960;